Melanocortin subtype-2 receptor (mc2r) antagonists and uses thereof

ABSTRACT

Described herein are compounds that are melanocortin subtype-2 receptor (MC2R) modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of MC2R activity.

RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 16/713,601, filed Dec. 13, 2019, which is a divisional applicationof U.S. application Ser. No. 16/432,228, filed Jun. 5, 2019, now U.S.Pat. No. 10,562,884, issued Feb. 28, 2020, which claims the benefit ofU.S. Provisional Patent Application No. 62/681,011 filed on Jun. 5,2018, and U.S. Provisional Patent Application No. 62/734,873 filed onSep. 21, 2018, each of which is herein incoporated by reference in itsentirety.

STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

This invention was made with government support under DK115245 awardedby the National Institutes of Health. The government has certain rightsin the invention.

FIELD OF THE INVENTION

Described herein are compounds that modulate the activity of one or moremelanocortin receptors, methods of making such compounds, pharmaceuticalcompositions and medicaments comprising such compounds, and methods ofusing such compounds in the treatment of conditions, diseases, ordisorders that would benefit from modulating melanocortin subtype-2receptor (MC2R) activity.

BACKGROUND OF THE INVENTION

The melanocortin receptors form a family of G protein-coupled receptor(GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectivelyactivated by different melanocortin peptides adrenocorticotropic hormone(ACTH), and the melanocortin peptides α-, β-, andγ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH) that are allderived proteolytically from proopiomelanocortin hormone, or POMC. ACTHis a 39 amino acid peptide that is the primary regulator of adrenalglucocorticoid synthesis and secretion and only has affinity for MC2R.As the central actor in this hypothalamic-pituitary-adrenal (HPA) axis,ACTH is secreted by the pituitary in response to stressful stimuli andacts at the adrenal gland to stimulate the synthesis and secretion ofcortisol. Modulation of MC2R is attractive for the treatment ofconditions, diseases, or disorders that would benefit from modulatingmelanocortin receptor activity.

SUMMARY OF THE INVENTION

Compounds described herein are melanocortin receptor modulatorcompounds. In some embodiments, compounds described herein modulate oneor more of the subtype melanocortin receptor proteins. In someembodiments, compounds described herein modulate two or more of thesubtype melanocortin receptor proteins. In some embodiments, compoundsdescribed herein modulate MC2R.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein:    -   R^(A) is unsubstituted or substituted phenyl, unsubstituted or        substituted monocyclic heteroaryl, wherein if R^(A) is        substituted then R^(A) is substituted with R^(a), R^(b) and        R^(c);    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, unsubstituted or substituted C₃-C₆        cycloalkyl, unsubstituted or substituted C₂-C₇ heterocycloalkyl,        unsubstituted or substituted phenyl or unsubstituted or        substituted monocyclic heteroaryl, wherein any substituted group        of R^(a), R^(b) and R^(c) is substituted with one or more R⁹        groups;    -   L is absent, —C(═O)—, —C(═O)NR⁷—, or —SO₂—;    -   R^(B) is unsubstituted or substituted carbocycle, unsubstituted        or substituted heterocycle, unsubstituted or substituted C₁-C₇        alkyl, unsubstituted or substituted C₁-C₇ fluoroalkyl,        unsubstituted or substituted C₁-C₆ heteroalkyl, wherein if R^(B)        is substituted then R^(B) is substituted with R^(d), R^(e) and        R^(f);    -   or R^(B) and R⁷ are taken together with the nitrogen atom to        which they are attached to form an unsubstituted or substituted        3- to 7-membered heterocycle, wherein if the 3- to 7-membered        heterocyle is substituted then the 3- to 7-membered heterocyle        is substituted with R^(d), R^(e) and R^(f);    -   R^(d), R^(e) and R^(f) are independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, unsubstituted or substituted C₃-C₆        cycloalkyl, unsubstituted or substituted C₂-C₇ heterocycloalkyl,        unsubstituted or substituted phenyl or unsubstituted or        substituted monocyclic heteroaryl, wherein any substituted group        of R^(d), R^(e) and R^(f) is substituted with one or more R⁹        groups;    -   X¹ is CR⁶ or N;    -   X² is CR⁶ or N;    -   X³ is CR⁶ or N;    -   R¹ is an unsubstituted or substituted C₁-C₆ alkyl, or        unsubstituted or substituted C₃-C₆ cycloalkyl, wherein if R¹ is        substituted then R¹ is substituted with hydrogen, —OR⁸, halogen,        —N(R⁷)₂, or —CN;    -   R² and R³ are independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, or unsubstituted or substituted        C₃-C₆cycloalkyl, wherein any substituted group of R² and R³ is        substituted with hydrogen, —OR⁸, —N(R⁷)₂, halogen, or —CN;    -   or R² and R³ are taken together with the carbon atom to which        they are attached to form —C(═O)—;    -   or R² and R³ are taken together with the carbon atom to which        they are attached to form an unsubstituted or substituted 3- to        6-membered monocyclic carbocycle;    -   R⁴ and R⁵ are independently selected from the group consisting        of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted monocyclic heterocycle,        unsubstituted or substituted —(C₁-C₆ alkyl)-carbocycle, or        unsubstituted or substituted —(C₁-C₆ alkyl)-heterocycle, wherein        any substituted group of R⁴ and R⁵ is substituted with one or        more halogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted monocyclic heterocycle, —N(R⁷)₂,        —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰,        —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂;    -   or R⁴ and R⁵ are taken together with the nitrogen atom to which        they are attached to form a substituted or unsubstituted 3- to        6-membered heterocycle, wherein if the 3- to 6-membered        heterocycle is substituted then the 3- to 6-membered heterocycle        is substituted with one or more halogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted monocyclic        heterocycle, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸,        —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or        —SO₂N(R⁷)₂;    -   or R² and R⁴ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        5- to 6-membered N-containing heterocycle; each R⁶ is        independently selected from the group consisting of hydrogen,        halogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted        or substituted C₃-C₆cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, —CN, —OR⁸, —SR⁸, —CO₂R⁸, —C(═O)N(R⁷)₂, or        —N(R⁷)₂;    -   each R⁷ is independently selected from the group consisting of        hydrogen, substituted C₁-C₆ alkyl, unsubstituted or substituted        C₃-C₆ cycloalkyl, unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl;    -   or two R⁷ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted 3- to        6-membered monocyclic heterocycle;    -   each R⁸ is independently selected from the group consisting of        hydrogen, substituted or substituted C₁-C₆ alkyl, unsubstituted        or substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted aryl, and        unsubstituted or substituted heteroaryl;    -   each R⁹ is independently hydrogen, halogen, unsubstituted or        substituted C₁-C₄alkyl, unsubstituted or substituted        C₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,        unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted or        substituted monocyclic carbocycle, unsubstituted or substituted        monocyclic heterocycle, —CN, —OH, —CO₂R⁸, —CH₂CO₂R⁸,        —C(═O)N(R⁷)₂, —C(═O)N(R⁷)OR⁸, —CH₂C(═O)N(R⁷)₂, —N(R⁷)₂,        —CH₂N(R⁷)₂, —C(R⁸)₂N(R⁷)₂, —NR⁷C(═O)R⁸, —CH₂NR⁷C(═O)R⁸,        —NR⁷C(═O)N(R⁷)₂, —NR⁷C(═O)N(R⁷)₂, C(R⁸)═N(R⁷)—OR⁸, —SR⁸,        —S(═O)R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂;    -   each R¹⁰ is independently selected from the group consisting        substituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted phenyl, and        unsubstituted or substituted heteroaryl;    -   n is 1 or 2.

Also described herein are pharmaceutical compositions comprising acompound described herein, or a pharmaceutically acceptable salt, orsolvate thereof, and at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical composition is formulated foradministration to a mammal by intravenous administration, subcutaneousadministration, oral administration, inhalation, nasal administration,dermal administration, or ophthalmic administration. In someembodiments, the pharmaceutical composition is formulated foradministration to a mammal by oral administration. In some embodiments,the pharmaceutical composition is in the form of a tablet, a pill, acapsule, a liquid, a suspension, a gel, a dispersion, a solution, anemulsion, an ointment, or a lotion. In some embodiments, thepharmaceutical composition is in the form of a tablet, a pill, or acapsule.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by inhalation; and/or (e) administered by nasaladministration; or and/or (f) administered by injection to the mammal;and/or (g) administered topically to the mammal; and/or (h) administeredby ophthalmic administration; and/or (i) administered rectally to themammal; and/or (j) adminstered non-systemically or locally to themammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which the compound is administered oncea day to the mammal or the compound is administered to the mammalmultiple times over the span of one day. In some embodiments, thecompound is administered on a continuous dosing schedule. In someembodiments, the compound is administered on a continuous daily dosingschedule.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are orally administeredto a human.

Articles of manufacture, which include packaging material, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, within thepackaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable salt, tautomers,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, is used for modulating one or more subtype melanocortinreceptor proteins, or for the treatment, prevention or amelioration ofone or more symptoms of a disease or condition that would benefit frommodulating one or more subtype melanocortin receptor proteins, areprovided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Adrenocorticotropic hormone (ACTH) is a 39 amino acid peptidesynthesized by anterior pituitary corticotrophic cells by proteolyticcleavage of the proopiomelanocortin hormone (POMC). ACTH is the primaryregulator of adrenal glucocorticoid (GC; cortisol in humans and mostother species; corticosterone in rodents) synthesis and secretion. Asthe central actor in this hypothalamic-pituitary-adrenal (HPA) axis,ACTH is secreted by the pituitary in response to stressful stimuli andacts at the adrenal gland to stimulate the synthesis and secretion ofcortisol. This stimulation is mediated through a highly specific Gprotein-coupled receptor (GPCR) which is expressed almost uniquely inthe adrenal cortex. The receptor is the melanocortin 2 receptor (MC2R),and, along with ACTH, is part of the larger melanocortin system.

The melanocortin system comprises a family of five GPCRs (MC1R, MC2R,MC3R, MC4R, and MC5R); their natural agonists, the melanocortin peptidesα-, β-, and γ-melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH)and ACTH; and endogenous melanocortin antagonists agouti andagouti-related protein (AGRP). The melanocortin receptors (MCRs) havedifferent selectivities for endogenous agonist and antagonist peptidesand are expressed in diverse tissues where they serve varied anddiscreet physiological functions (Gantz, I. and T. M. Fong, Am. J.Physiol. Endocrinol. Metab., 284: E468-E474, 2003).

It is possible to selectively modulate any one of the MCRs, orcombinations thereof. In some embodiments, selectively modulating anyone of the MCRs relative to the other MCRs, or combinations thereof, isuseful in a variety of clinical applications. In some embodiments,selectively modulating any one of the MCRs relative to the other MCRs,or combinations thereof, reduces unwanted side effects in a variety ofclinical applications. In one aspect, compounds described herein areantagonists of MC2R. In some embodiments, compounds described herein areselective antagonists for MC2R relative or other MCRs.

MC2R is a highly selective receptor for ACTH. Although ACTH can activateall five MCRs, at physiological levels, the sensitivity of the otherreceptors is not high enough to be activated, and ACTH selectivelyactivates MC2R. Importantly, the other naturally occurring agonistsα-MSH, β-MSH, and β-MSH have no affinity for MC2R (Gantz, I. and T. M.Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003). Themajor function of MC2R is to stimulate the fasciculata cells of theadrenal cortex to synthesize and secret cortisol. MC2R requires the GPCRaccessory protein MRAP (melanocortin 2 receptor protein) to besuccessfully secreted to the cell surface and as well as to function.MRAP is a small protein with a single transmembrane domain that forms anantiparallel homodimer in stable complex with MC2R and is necessary forboth cell surface expression of MC2R and its ability to bind ACTH. MRAPcan bind to any of the MCRs and affect their activities, but is onlyessential for MC2R activity. Binding of ACTH to the MC2R/MRAP complex onadrenal cortical cells activates Gs to elevate intracellular cAMP levelswhich in turn stimulates cortisol synthesis and secretion by regulatingmultiple steps in the steroidogenic pathway.

Cushing's syndrome is a rare disorder characterized by chronic, excessglucocorticoid exposure. Clinical signs of Cushing's syndrome includegrowth of fat pads (collarbone, back of neck, face and trunk), excessivesweating, dilation of capillaries, thinning of the skin, muscleweakness, hirsutism, depression/anxiety, hypertension, osteoporosis,insulin resistance, hyperglycemia, heart disease, and a range of othermetabolic disturbances resulting in high morbidity. If inadequatelycontrolled in its severe forms, Cushing's syndrome is associated withhigh mortality. Although glucocorticoid excess can sometimes be ACTHindependent, for example from excessive autonomous secretion of cortisolfrom a hyperfunctioning adrenal adenoma, carcinoma, or steroid abuse,about 60-80% of all cases are ACTH dependent Cushing's syndrome, knownas Cushing's disease. Cushing's disease is caused by microadenomas ofpituitary corticotropic cells that secrete excess ACTH. Corticotrophadenomas are small, usually slow growing, benign tumors that normallycome to clinical attention as a result of the effects of glucocorticoidexcess, rather than because of the physical effects of an expandingtumor. First line treatments for Cushing's disease are surgical andinvolve removal of either the ACTH-secreting tumor in the pituitary orthe adrenal glands themselves. As surgery is often unsuccessful,contraindicated, or delayed, medical therapy for these patients becomesnecessary. Current treatment options include inhibitors of steroidsynthesis enzymes that can prevent the production of cortisol andimprove symptoms, but these treatments also induce a host of unwantedside effects due to the accumulation of other steroid products. In oneaspect, an MC2R antagonist is used in the treatment of Cushing'ssyndrome. In some embodiments, an MC2R antagonist is used in thetreatment of Cushing's disease. In some embodiments, glucocorticoidexcess is ACTH independent. In some embodiments, glucocorticoid excessis ACTH dependent.

Ectopic ACTH syndrome, or ectopic Cushing's syndrome or disease, isessentially the same as Cushing's disease, except that the underlyingtumor expressing ACTH is outside the pituitary gland. In someembodiments, the tumors are small carcinoid tumors that occur anywherein the lungs or gastrointestinal tract. In some embodiments, an MC2Rantagonist is used in the treatment of ectopic ACTH syndrome.

Congenital adrenal hyperplasia (CAH) is characterized by a reduction orloss of cortisol synthesis and excessive ACTH andcorticotropin-releasing hormone. CAH can result from a variety ofgenetic defects in the adrenal steroidal biosynthesis pathway. In someembodiments, CAH is due to a mutation in 210-hydroxylase. The lack ofcortisol removes the negative feedback to the pituitary which leads toexcessive ACTH secretion. The resulting excessive adrenal stimulationcauses overproduction of steroid precursors which also have negativeconsequences (e.g., hyperandrogenism). Administration of replacementglucocorticoids typically does not adequately suppress ACTH without alsocausing Cushing's-like symptoms. In some embodiments, an MC2R antagonistis used in the treatment of CAH.

In addition to Cushing's disease and CAH it has also been hypothesizedthat there might be a role for an MC2R antagonist in the treatment ofdepressive illness and septic shock. In some embodiments, an MC2Rantagonist is used in the treatment of depressive illness. In someembodiments, an MC2R antagonist is used in the treatment of septicshock.

In some embodiments, compounds described herein are amenable toadministration to a mammal in need of treatment with an MC2R antagonist.

Compounds

Compounds of Formula (I), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are melanocortin receptor modulators. In some embodiments, thecompounds of Formula (I), including pharmaceutically acceptable salts,prodrugs, active metabolites and pharmaceutically acceptable solvatesthereof, are MC2R modulators. In some embodiments, the MC2R modulatorsare MC2R antagonists.

Provided in one aspect is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

-   -   wherein:    -   R^(A) is unsubstituted or substituted phenyl, unsubstituted or        substituted monocyclic heteroaryl, wherein if R^(A) is        substituted then R^(A) is substituted with R^(a), R^(b) and        R^(c);    -   R^(a), R^(b) and R^(c) are independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, unsubstituted or substituted C₃-C₆        cycloalkyl, unsubstituted or substituted C₂-C₇ heterocycloalkyl,        unsubstituted or substituted phenyl or unsubstituted or        substituted monocyclic heteroaryl, wherein any substituted group        of R^(a), R^(b) and R^(c) is substituted with one or more R⁹        groups;    -   L is absent, —C(═O)—, —C(═O)NR⁷—, or —SO₂—;    -   R^(B) is unsubstituted or substituted carbocycle, unsubstituted        or substituted heterocycle, unsubstituted or substituted C₁-C₇        alkyl, unsubstituted or substituted C₁-C₇ fluoroalkyl,        unsubstituted or substituted C₁-C₆ heteroalkyl, wherein if R^(B)        is substituted then R^(B) is substituted with R^(d), R^(e) and        R^(f);    -   or R^(B) and R⁷ are taken together with the nitrogen atom to        which they are attached to form an unsubstituted or substituted        3- to 7-membered heterocycle, wherein if the 3- to 7-membered        heterocyle is substituted then the 3- to 7-membered heterocyle        is substituted with R^(d), R^(e) and R^(f);    -   R^(d), R^(e) and R^(f) are independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, unsubstituted or substituted C₃-C₆        cycloalkyl, unsubstituted or substituted C₂-C₇ heterocycloalkyl,        unsubstituted or substituted phenyl or unsubstituted or        substituted monocyclic heteroaryl, wherein any substituted group        of R^(d), R^(e) and R^(f) is substituted with one or more R⁹        groups;    -   X¹ is CR⁶ or N;    -   X² is CR⁶ or N;    -   X³ is CR⁶ or N;    -   R¹ is an unsubstituted or substituted C₁-C₆ alkyl, or        unsubstituted or substituted C₃-C₆ cycloalkyl, wherein if R¹ is        substituted then R¹ is substituted with hydrogen, —OR⁸, halogen,        —N(R⁷)₂, or —CN;    -   R² and R³ are independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, or unsubstituted or substituted        C₃-C₆cycloalkyl, wherein any substituted group of R² and R³ is        substituted with hydrogen, —OR⁸, —N(R⁷)₂, halogen, or —CN;    -   or R² and R³ are taken together with the carbon atom to which        they are attached to form —C(═O)—;    -   or R² and R³ are taken together with the carbon atom to which        they are attached to form an unsubstituted or substituted 3- to        6-membered monocyclic carbocycle;    -   R⁴ and R⁵ are independently selected from the group consisting        of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted monocyclic carbocycle,        unsubstituted or substituted monocyclic heterocycle,        unsubstituted or substituted —(C₁-C₆ alkyl)-carbocycle, or        unsubstituted or substituted —(C₁-C₆ alkyl)-heterocycle, wherein        any substituted group of R⁴ and R⁵ is substituted with one or        more halogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted monocyclic heterocycle, —N(R⁷)₂,        —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰,        —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂;    -   or R⁴ and R⁵ are taken together with the nitrogen atom to which        they are attached to form a substituted or unsubstituted 3- to        6-membered heterocycle, wherein if the 3- to 6-membered        heterocycle is substituted then the 3- to 6-membered heterocycle        is substituted with one or more halogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted monocyclic        heterocycle, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸,        —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or        —SO₂N(R⁷)₂;    -   or R² and R⁴ are taken together with the intervening atoms to        which they are attached to form a substituted or unsubstituted        5- to 6-membered N-containing heterocycle;    -   each R⁶ is independently selected from the group consisting of        hydrogen, halogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₃-C₆cycloalkyl, unsubstituted or        substituted C₁-C₆fluoroalkyl, —CN, —OR⁸, —SR⁸, —CO₂R⁸,        —C(═O)N(R⁷)₂, or —N(R⁷)₂;    -   each R⁷ is independently selected from the group consisting of        hydrogen, substituted C₁-C₆ alkyl, unsubstituted or substituted        C₃-C₆ cycloalkyl, unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl;    -   or two R⁷ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted 3- to        6-membered monocyclic heterocycle;    -   each R⁸ is independently selected from the group consisting of        hydrogen, substituted or substituted C₁-C₆ alkyl, unsubstituted        or substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted aryl, and        unsubstituted or substituted heteroaryl;    -   each R⁹ is independently hydrogen, halogen, unsubstituted or        substituted C₁-C₄alkyl, unsubstituted or substituted        C₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,        unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted or        substituted monocyclic carbocycle, unsubstituted or substituted        monocyclic heterocycle, —CN, —OH, —CO₂R⁸, —CH₂CO₂R⁸,        —C(═O)N(R⁷)₂, —C(═O)N(R⁷)OR⁸, —CH₂C(═O)N(R⁷)₂, —N(R⁷)₂,        —CH₂N(R⁷)₂, —C(R⁸)₂N(R⁷)₂, —NR⁷C(═O)R⁸, —CH₂NR⁷C(═O)R⁸,        —NR⁷C(═O)N(R⁷)₂, —NR⁷C(═O)N(R⁷)₂, C(R⁸)═N(R⁷)—OR⁸, —SR⁸,        —S(═O)R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂;    -   each R¹⁰ is independently selected from the group consisting        substituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted phenyl, and        unsubstituted or substituted heteroaryl;    -   n is 1 or 2.

In some embodiments, L is absent, —C(═O)—, —C(═O)NR⁷—, or —SO₂—. In someembodiments, L is absent, —C(═O)—, or —C(═O)NR⁷—. In some embodiments, Lis —C(═O)— or —C(═O)NR⁷—. In some embodiments, L is —C(═O)—. In someembodiments, L is —C(═O)NR⁷—.

In some embodiments, L is —C(═O)—; R² and R³ are independently hydrogen,—CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂OR⁸, or —CH₂NHR⁷; or R² and R³ are takentogether with the carbon atom to which they are attached to form—C(═O)—. In some embodiments, R² and R³ are hydrogen; or R² and R³ aretaken together with the carbon atom to which they are attached to form—C(═O)—. In some embodiments, R² and R³ are hydrogen. In someembodiments, R² and R³ are taken together with the carbon atom to whichthey are attached to form —C(═O)—.

In some embodiments, L is —C(═O)—; R² and R³ are independently hydrogenor —CH₃; or R² and R³ are taken together with the carbon atom to whichthey are attached to form —C(═O)—; or R² and R³ are taken together withthe carbon atom to which they are attached to form a cyclopropyl.

In some embodiments, R^(A) is unsubstituted or substituted phenyl,unsubstituted or substituted monocyclic 6-membered heteroaryl,unsubstituted or substituted monocyclic 5-membered heteroaryl, whereinif R^(A) is substituted then R^(A) is substituted with R^(a), R^(b) andR^(c).

In some embodiments, R^(A) is unsubstituted or substituted phenyl,unsubstituted or substituted pyridinyl, unsubstituted or substitutedpyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted orsubstituted pyridazinyl, unsubstituted or substituted triazinyl,unsubstituted or substituted furanyl, unsubstituted or substitutedthienyl, unsubstituted or substituted pyrrolyl, unsubstituted orsubstituted oxazolyl, unsubstituted or substituted thiazolyl,unsubstituted or substituted imidazolyl, unsubstituted or substitutedpyrazolyl, unsubstituted or substituted triazolyl, unsubstituted orsubstituted tetrazolyl, unsubstituted or substituted isoxazolyl,unsubstituted or substituted isothiazolyl, unsubstituted or substitutedoxadiazolyl, or unsubstituted or substituted thiadiazolyl; wherein ifR^(A) is substituted then R^(A) is substituted with R^(a), R^(b) andR^(c).

In some embodiments, R^(A) is unsubstituted or substituted phenyl,unsubstituted or substituted pyridinyl, unsubstituted or substitutedpyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted orsubstituted pyridazinyl; wherein if R^(A) is substituted then R^(A) issubstituted with R^(a), R^(b) and R^(c).

In some embodiments, R^(A) is unsubstituted or substituted phenyl, orunsubstituted or substituted pyridinyl, wherein if R^(A) is substitutedthen R^(A) is substituted with R^(a), R^(b) and R^(c).

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

where V is CH or N.

In some embodiments, R^(A) is

where V is CH or N. In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, n is 1. In some embodiments, n is 2.

In some embodiments, the compound has the structure of Formula (II), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   V is CH or N.

In some embodiments, R^(B) is an unsubstituted or substituted monocycliccarbocycle, unsubstituted or substituted bicyclic carbocycle,unsubstituted or substituted polycyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substitutedbicyclic heterocycle, unsubstituted or substituted polycyclicheterocycle, wherein if R^(B) is substituted then R^(B) is substitutedwith R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is an unsubstituted or substituted monocycliccarbocycle, unsubstituted or substituted bridged carbocycle,unsubstituted or substituted spiro carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substituted bridgedheterocycle, unsubstituted or substituted spiro heterocycle, wherein ifR^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f).

In some embodiments, R^(B) is an unsubstituted or substituted phenyl,unsubstituted or substituted naphthyl, unsubstituted or substitutedmonocyclic 6-membered heteroaryl, unsubstituted or substitutedmonocyclic 5-membered heteroaryl, unsubstituted or substituted bicyclicheteroaryl, monocyclic C₃-C₈cycloalkyl, unsubstituted or substitutedbridged C₅-C₁₀cycloalkyl, unsubstituted or substituted spiroC₅-C₁₀cycloalkyl, unsubstituted or substituted monocyclicC₂-C₈heterocycloalkyl, unsubstituted or substituted bridgedC₅-C₁₀heterocycloalkyl, or unsubstituted or substituted spiroC₅-C₁₀heterocycloalkyl, wherein if R^(B) is substituted then R^(B) issubstituted with R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is an unsubstituted or substituted carbocyclethat is an unsubstituted or substituted phenyl, unsubstituted orsubstituted naphthyl, unsubstituted or substituted indanyl,unsubstituted or substituted indenyl, unsubstituted or substitutedtetrahyodronaphthyl, unsubstituted or substituted cyclopropyl,unsubstituted or substituted cyclobutyl, unsubstituted or substitutedcyclopentyl, unsubstituted or substituted cyclopentenyl, unsubstitutedor substituted cyclohexyl, unsubstituted or substituted cyclohexenyl,unsubstituted or substituted cycloheptyl, unsubstituted or substitutedcyclooctyl, unsubstituted or substituted spiro[2.2]pentyl, unsubstitutedor substituted spiro[3.3]heptyl, unsubstituted or substitutedspiro[3.5]nonyl, unsubstituted or substituted spiro[4.4]nonyl,unsubstituted or substituted spiro[4.5]decyl, unsubstituted orsubstituted norbornyl, unsubstituted or substituted norbornenyl,unsubstituted or substituted bicyclo[1.1.1]pentyl, unsubstituted orsubstituted adamantyl, or unsubstituted or substituted decalinyl.

In some embodiments, R^(B) is an unsubstituted or substituted furanyl,unsubstituted or substituted thienyl, unsubstituted or substitutedpyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted orsubstituted thiazolyl, unsubstituted or substituted imidazolyl,unsubstituted or substituted pyrazolyl, unsubstituted or substitutedtriazolyl, unsubstituted or substituted tetrazolyl, unsubstituted orsubstituted isoxazolyl, unsubstituted or substituted isothiazolyl,unsubstituted or substituted oxadiazolyl, unsubstituted or substitutedthiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted orsubstituted pyrimidinyl, unsubstituted or substituted pyrazinyl,unsubstituted or substituted pyridazinyl, unsubstituted or substitutedtriazinyl, unsubstituted or substituted quinolinyl, unsubstituted orsubstituted isoquinolinyl, unsubstituted or substituted cinnolinyl,unsubstituted or substituted phthalazinyl, unsubstituted or substitutedquinazolinyl, unsubstituted or substituted quinoxalinyl, unsubstitutedor substituted naphthyridinyl, unsubstituted or substituted pteridinyl,unsubstituted or substituted indolizinyl, unsubstituted or substitutedazaindolizinyl, unsubstituted or substituted indolyl, unsubstituted orsubstituted azaindolyl, unsubstituted or substituted indazolyl,unsubstituted or substituted azaindazolyl, unsubstituted or substitutedbenzimidazolyl, unsubstituted or substituted azabenzimidazolyl,unsubstituted or substituted benzotriazolyl, unsubstituted orsubstituted azabenzotriazolyl, unsubstituted or substitutedbenzoxazolyl, unsubstituted or substituted azabenzoxazolyl,unsubstituted or substituted benzisoxazolyl, unsubstituted orsubstituted azabenzisoxazolyl, unsubstituted or substitutedbenzofuranyl, unsubstituted or substituted azabenzofuranyl,unsubstituted or substituted benzothienyl, unsubstituted or substitutedazabenzothienyl, unsubstituted or substituted benzothiazolyl,unsubstituted or substituted azabenzothiazolyl, or unsubstituted orsubstituted purinyl. In some embodiments, R^(B) is an unsubstituted orsubstituted indolyl, wherein if R^(B) is substituted then R^(B) issubstituted with R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is an unsubstituted or substitutedaziridinyl, unsubstituted or substituted azetidinyl, unsubstituted orsubstituted oxetanyl, unsubstituted or substituted thietanyl,unsubstituted or substituted pyrrolidinyl, unsubstituted or substitutedtetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl,unsubstituted or substituted oxazolidinonyl, unsubstituted orsubstituted tetrahydropyranyl, unsubstituted or substituted piperidinyl,unsubstituted or substituted morpholinyl, unsubstituted or substitutedthiomorpholinyl, unsubstituted or substituted piperazinyl, unsubstitutedor substituted homopiperidinyl, unsubstituted or substituted oxepanyl,unsubstituted or substituted thiepanyl, unsubstituted or substitutedoxazepinyl, unsubstituted or substituted diazepinyl, unsubstituted orsubstituted thiazepinyl, unsubstituted or substitutedazaspiro[3.3]heptanyl, unsubstituted or substitutedazaspiro[3.4]octanyl, unsubstituted or substituted azaspiro[3.4]octanyl,or unsubstituted or substituted azaspiro[4.4]nonyl.

In some embodiments, R^(B) is unsubstituted or substituted phenyl,unsubstituted or substituted pyridinyl, unsubstituted or substitutedpyrimidinyl, unsubstituted or substituted pyrazinyl, or unsubstituted orsubstituted pyridazinyl, wherein if R^(B) is substituted then R^(B) issubstituted with R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is unsubstituted or substituted cyclopropyl,unsubstituted or substituted cyclobutyl, unsubstituted or substitutedcyclopentyl, unsubstituted or substituted cyclopentenyl, orunsubstituted or substituted cyclohexyl, wherein if R^(B) is substitutedthen R^(B) is substituted with R^(d), R^(e) and R^(f). In someembodiments, R^(B) is unsubstituted or substituted cyclobutyl, whereinif R^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f).

In some embodiments, R^(B) is an unsubstituted or substitutedaziridinyl, unsubstituted or substituted azetidinyl, unsubstituted orsubstituted oxetanyl, unsubstituted or substituted thietanyl,unsubstituted or substituted pyrrolidinyl, unsubstituted or substitutedtetrahydrofuranyl, unsubstituted or substituted tetrahydrothienyl,unsubstituted or substituted oxazolidinonyl, unsubstituted orsubstituted tetrahydropyranyl, unsubstituted or substituted piperidinyl,unsubstituted or substituted morpholinyl, unsubstituted or substitutedthiomorpholinyl, or unsubstituted or substituted piperazinyl, wherein ifR^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f). In some embodiments, R^(B) is an unsubstituted or substitutedaziridinyl, unsubstituted or substituted azetidinyl, unsubstituted orsubstituted pyrrolidinyl, unsubstituted or substituted piperidinyl,unsubstituted or substituted morpholinyl, unsubstituted or substitutedthiomorpholinyl, or unsubstituted or substituted piperazinyl, wherein ifR^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f). In some embodiments, R^(B) is an unsubstituted or substitutedpyrrolidinyl, wherein if R^(B) is substituted then R^(B) is substitutedwith R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is

where m is 0, 1, 2, or 3. In some embodiments, m is 2 or 3. In someembodiments, m is 0. In some embodiments, m is 1. In some embodiments, mis 2. In some embodiments, m is 3.

In some embodiments, R^(B) is unsubstituted or substituted phenyl, orunsubstituted or substituted pyridinyl, wherein if R^(B) is substitutedthen R^(B) is substituted with R^(d), R^(e) and R^(f).

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

In some embodiments, R^(B) is

where Z is CH or N. In some embodiments, R^(B) is

where Z is CH or N.

In some embodiments, the compound has the structure of Formula (III), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein,    -   V is CH or N;    -   Z is CH or N.

In some embodiments, the compound has the structure of Formula (IV), ora pharmaceutically acceptable salt, or solvate thereof:

In some embodiments, the compound has the structure of Formula (V), or apharmaceutically acceptable salt, or solvate thereof:

In some embodiments, R¹ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂CN, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃,—CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NH₂,—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl.

In some embodiments, R¹ is —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃.

In some embodiments, R⁴ is selected from the group consisting ofhydrogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substitutedmonocyclic heterocycle, unsubstituted or substituted —(C₁-C₆alkyl)-carbocycle, or unsubstituted or substituted —(C₁-C₆alkyl)-heterocycle, wherein any substituted group of R⁴ is substitutedwith one or more halogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted monocyclic heterocycle, —N(R⁷)₂, —OR⁸, —CN,—CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸,—NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; R⁵ is selected from the groupconsisting of hydrogen, and C₁-C₆ alkyl; or R⁴ and R⁵ are taken togetherwith the nitrogen atom to which they are attached to form a substitutedor unsubstituted 3- to 6-membered heterocycle, wherein if the 3- to6-membered heterocycle is substituted then the 3- to 6-memberedheterocycle is substituted with one or more halogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted monocyclicheterocycle, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂.

In some embodiments, R⁴ is selected from the group consisting ofhydrogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0or 1 O or S atoms, wherein any substituted group of R⁴ is substitutedwith one or more halogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocyclecontaining 1-4 N atoms and 0 or 1 O or S atoms, —N(R⁷)₂, —OR⁸, —CN,—CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸,—NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; R⁵ is selected from the groupconsisting of hydrogen, —CH₃, —CH₂CH₃, and —CH₂CH₂CH₃.

In some embodiments, R⁴ is selected from the group consisting ofhydrogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted monocyclic carbocycle, or unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0or 1 O or S atoms, wherein any substituted group of R⁴ is substitutedwith one or more halogen, C₁-C₆ alkyl that is unsubstituted orsubstituted with a heterocycle, unsubstituted or substituted monocyclic4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O orS atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; R⁵ isselected from the group consisting of hydrogen, —CH₃, —CH₂CH₃, and—CH₂CH₂CH₃. In some embodiments, R⁴ is unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0or 1 O or S atoms, wherein any substituted group of R⁴ is substitutedwith one or more halogen, C₁-C₆ alkyl that is unsubstituted orsubstituted with a heterocycle, unsubstituted or substituted monocyclic4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0 or 1 O orS atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰,—S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; R⁵ isselected from the group consisting of hydrogen, —CH₃, —CH₂CH₃, and—CH₂CH₂CH₃. In some embodiments, R⁴ is unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0or 1 O or S atoms, wherein any substituted group of R⁴ is substitutedwith one or more halogen, C₁-C₆ alkyl that is unsubstituted orsubstituted with a 1,3-dioxol-2-one group, unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-4 N atoms and 0or 1 O or S atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸,—S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂;R⁵ is selected from the group consisting of hydrogen, —CH₃, —CH₂CH₃, and—CH₂CH₂CH₃.

In some embodiments, the compound has the structure of Formula (VI), ora pharmaceutically acceptable salt, or solvate thereof:

In some embodiments, the compound has the structure of Formula (VII), ora pharmaceutically acceptable salt, or solvate thereof:

-   -   wherein:    -   R^(A) is unsubstituted or substituted phenyl, or unsubstituted        or substituted pyridinyl, wherein if R^(A) is substituted then        R^(A) is substituted with R^(a), R^(b) and R^(c);    -   L is absent, —C(═O)—, or —C(═O)NR⁷—;    -   R^(B) is unsubstituted or substituted carbocycle, unsubstituted        or substituted heterocycle, wherein if R^(B) is substituted then        R^(B) is substituted with R^(d), R^(e) and R^(f);    -   or R^(B) and R⁷ are taken together with the nitrogen atom to        which they are attached to form an unsubstituted or substituted        3- to 7-membered heterocycle, wherein if the 3- to 7-membered        heterocyle is substituted then the 3- to 7-membered heterocyle        is substituted with R^(d), R^(e) and R^(f).

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, R^(A) is

In some embodiments, X¹ is CR⁶; X² is CR⁶; X³ is CR⁶.

In some embodiments, X¹ is N; X² is CR⁶; X³ is CR⁶.

In some embodiments, X¹ is CR⁶; X² is N; X³ is CR⁶.

In some embodiments, X¹ is CR⁶; X² is CR⁶; X³ is N.

In some embodiments, each R⁶ is independently selected from the groupconsisting of hydrogen, halogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆fluoroalkyl, —CN, and —OR⁸. Insome embodiments, each R⁶ is independently selected from the groupconsisting of hydrogen, halogen, and unsubstituted or substituted C₁-C₆alkyl. In some embodiments, each R⁶ is independently selected from thegroup consisting of hydrogen and halogen. In some embodiments, each R⁶is independently selected from the group consisting of hydrogen andfluorine.

In some embodiments, X¹ is CH, CF, or N; X² is CH, CF, or N; and X³ isCH, CF, or N.

In some embodiments, R⁴ is an unsubstituted or substituted C₁-C₆ alkylor unsubstituted or substituted monocyclic 4-, 5- or 6-memberedheterocycle containing 1-2 N atoms and 0 or 1 O or S atoms, wherein anysubstituted group of R⁴ is substituted with one or more halogen,unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 Natoms and 0 or 1 O or S atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂,—SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or—SO₂N(R⁷)₂.

In some embodiments, R⁴ is an unsubstituted or substituted C₁-C₆ alkyl,wherein any substituted group of R⁴ is substituted with one or morehalogen, unsubstituted or substituted C₁-C₆ alkyl, or unsubstituted orsubstituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 Natoms and 0 or 1 O or S atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂,—SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or—SO₂N(R⁷)₂.

In some embodiments, R⁴ is an unsubstituted or substituted monocyclic4-, 5- or 6-membered heterocycle containing 1-2 N atoms and 0 or 1 O orS atoms, wherein any substituted group of R⁴ is substituted with one ormore halogen, unsubstituted or substituted C₁-C₆ alkyl, —N(R⁷)₂, —OR⁸,—CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸,—NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂. In some embodiments, R⁴ is anunsubstituted or substituted monocyclic 4-, 5- or 6-membered heterocyclecontaining 1-2 N atoms and 0 or 1 O or S atoms, wherein any substitutedgroup of R⁴ is substituted with one or more halogen, unsubstituted orsubstituted C₁-C₆ alkyl, —N(R⁷)₂, —OR⁸, or —CN. In some embodiments, R⁴is an unsubstituted or substituted monocyclic 4-, 5- or 6-memberedheterocycle containing 1 atom, wherein any substituted group of R⁴ issubstituted with one or more halogen, unsubstituted or substituted C₁-C₆alkyl, —N(R⁷)₂, —OR⁸, or —CN.

In some embodiments, R^(a) is selected from the group consisting ofhydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,unsubstituted or substituted C₁-C₆ heteroalkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, wherein any substituted group of R^(a) issubstituted with one or more R⁹ groups; R^(b) and R^(c) areindependently selected from the group consisting of hydrogen, halogen,—OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ fluoroalkyl, unsubstituted orsubstituted C₁-C₆ heteroalkyl, wherein any substituted group of R^(b)and R^(c) is substituted with one or more R⁹ groups.

In some embodiments, R^(a) is hydrogen, Cl, Br, —CN, —OH, —OCH₃,—OCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂OH, —CH₂CN, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂OH, —CH₂CH₂CN, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂OCH₃,—CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;R^(b) and R^(c) are independently selected from the group consisting ofhydrogen, Cl, Br, —CN, —OH, —OCH₃, —OCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃,—CH₂OH, —CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂CN, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂NHCH₃, or —CH₂CH₂N(CH₃)₂.

In some embodiments, R^(d) is selected from the group consisting ofhydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,unsubstituted or substituted C₁-C₆ heteroalkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, unsubstituted or substituted C₂-C₇heterocycloalkyl, unsubstituted or substituted phenyl or unsubstitutedor substituted monocyclic heteroaryl, wherein any substituted group ofR^(d) is substituted with one or more R⁹ groups; R^(e) and R^(f) areindependently selected from the group consisting of hydrogen, halogen,—OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ fluoroalkyl, unsubstituted orsubstituted C₁-C₆ heteroalkyl, wherein any substituted group of R^(e)and R^(f) is substituted with one or more R⁹ groups. In someembodiments, R^(d) is selected from the group consisting of hydrogen,halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ fluoroalkyl, and unsubstituted orsubstituted C₁-C₆ heteroalkyl, wherein any substituted group of R^(d) issubstituted with one or more R⁹ groups; and R^(e) and R^(f) are eachindependently selected from the group consisting of hydrogen, halogen,—OR⁸, —CN, —N(R⁷)₂, and unsubstituted or substituted C₁-C₆ alkyl,wherein any substituted group of R^(e) and R^(f) is substituted with oneor more R⁹ groups.

In some embodiments, R^(d) is selected from the group consisting ofhydrogen, Cl, Br, —CN, —OH, —OCH₃, —OCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃,—CH₂OH, —CH₂CN, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂CN, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃,—CH₂N(CH₃)₂, —CH₂CH₂NH₂, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, unsubstituted orsubstituted cyclopropyl, unsubstituted or substituted cyclobutyl,unsubstituted or substituted cyclopentyl, unsubstituted or substitutedcyclohexyl, unsubstituted or substituted C₂-C₇ heterocycloalkyl,unsubstituted or substituted phenyl or unsubstituted or substitutedmonocyclic heteroaryl, wherein any substituted group of R^(d) issubstituted with one or more R⁹ groups; R^(e) and R^(f) areindependently selected from the group consisting of F, Cl, Br, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂,—CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂OH, —CH₂CN, —CH₂F, —CHF₂, —CF₃, —CN,—OH, —OCH₃, and —OCH₂CH₃.

In some embodiments, the compound has the structure of Formula (VIII),or a pharmaceutically acceptable salt, or solvate thereof:

In some embodiments, R^(A), R^(B), R⁴, and X¹ are as described in Table1, Table 2 or Table 3.

In some embodiments, the compound of Formula (I) or Formula (II) has thestructure of Formula (IX), or a pharmaceutically acceptable salt, orsolvate thereof:

-   -   wherein,    -   V is CH or N.

In some embodiments, the compound has the structure of Formula (IX), ora pharmaceutically acceptable salt, or solvate thereof, wherein:

-   -   V is CH or N;    -   R^(a) is selected from the group consisting of hydrogen,        halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆        alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,        unsubstituted or substituted C₁-C₆ heteroalkyl, unsubstituted or        substituted C₃-C₆ cycloalkyl, wherein any substituted group of        R^(a) is substituted with one or more R⁹ groups;    -   R^(b) and R^(c) are each independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, wherein any substituted group of R^(b) and        R^(c) is substituted with one or more R⁹ groups;    -   R^(B) is unsubstituted or substituted carbocycle, unsubstituted        or substituted heterocycle, unsubstituted or substituted C₁-C₇        alkyl, unsubstituted or substituted C₁-C₇ fluoroalkyl,        unsubstituted or substituted C₁-C₆ heteroalkyl, wherein if R^(B)        is substituted then R^(B) is substituted with R^(d), R^(e) and        R^(f);    -   R^(d) is selected from the group consisting of hydrogen,        halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆        alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,        unsubstituted or substituted C₁-C₆ heteroalkyl, unsubstituted or        substituted C₃-C₆ cycloalkyl, unsubstituted or substituted C₂-C₇        heterocycloalkyl, unsubstituted or substituted phenyl or        unsubstituted or substituted monocyclic heteroaryl, wherein any        substituted group of R^(d) is substituted with one or more R⁹        groups;    -   R^(e) and R^(f) are each independently selected from the group        consisting of hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₁-C₆ fluoroalkyl, unsubstituted or substituted        C₁-C₆ heteroalkyl, wherein any substituted group of R^(e) and        R^(f) is substituted with one or more R⁹ groups;    -   X¹ is CR⁶ or N;    -   R² and R³ are hydrogen;    -   or R² and R³ are taken together with the carbon atom to which        they are attached to form —C(═O)—;    -   R⁴ is selected from the group consisting of hydrogen,        unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted monocyclic carbocycle, unsubstituted or substituted        monocyclic heterocycle, unsubstituted or substituted —(C₁-C₆        alkyl)-carbocycle, or unsubstituted or substituted —(C₁-C₆        alkyl)-heterocycle, wherein any substituted group of R⁴ is        substituted with one or more halogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted monocyclic        heterocycle, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸,        —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or        —SO₂N(R⁷)₂;    -   R⁶ is H or F;    -   each R⁷ is independently selected from the group consisting of        hydrogen, substituted C₁-C₆ alkyl, unsubstituted or substituted        C₃-C₆ cycloalkyl, unsubstituted or substituted C₁-C₆fluoroalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl;    -   or two R⁷ are taken together with the nitrogen atom to which        they are attached to form an unsubstituted or substituted 3- to        6-membered monocyclic heterocycle;    -   each R⁸ is independently selected from the group consisting of        hydrogen, substituted or substituted C₁-C₆ alkyl, unsubstituted        or substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted aryl, and        unsubstituted or substituted heteroaryl;    -   each R⁹ is independently hydrogen, halogen, unsubstituted or        substituted C₁-C₄alkyl, unsubstituted or substituted        C₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,        unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted or        substituted monocyclic carbocycle, unsubstituted or substituted        monocyclic heterocycle, —CN, —OH, —CO₂R⁸, —CH₂CO₂R⁸,        —C(═O)N(R⁷)₂, —C(═O)N(R⁷)OR⁸, —CH₂C(═O)N(R⁷)₂, —N(R⁷)₂,        —CH₂N(R⁷)₂, —C(R⁸)₂N(R⁷)₂, —NR⁷C(═O)R⁸, —CH₂NR⁷C(═O)R⁸,        —NR⁷C(═O)N(R⁷)₂, —NR⁷C(═O)N(R⁷)₂, C(R⁸)═N(R⁷)—OR⁸, —SR⁸,        —S(═O)R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; and    -   each R¹⁰ is independently selected from the group consisting        substituted or substituted C₁-C₆ alkyl, unsubstituted or        substituted C₃-C₆ cycloalkyl, unsubstituted or substituted        C₁-C₆fluoroalkyl, unsubstituted or substituted phenyl, and        unsubstituted or substituted heteroaryl.

In some embodiments, V is CH. In some embodiments, V is N.

In some embodiments, R^(a) is selected from the group consisting ofhydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl, andunsubstituted or substituted C₁-C₆ heteroalkyl, wherein any substitutedgroup of R^(a) is substituted with one or more R⁹ groups; and R^(b) andR^(c) are each independently selected from the group consisting ofhydrogen, halogen, —OR⁸, —N(R⁷)₂, and unsubstituted or substituted C₁-C₆alkyl, wherein any substituted group of R^(b) and R^(c) is substitutedwith one or more R⁹ groups. In some embodiments, R^(a) is hydrogen, Cl,Br, —CN, —OH, —OCH₃, —OCH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —CH(CH₃)(CH₂CH₃), —C(CH₃)₃, —CH₂OH, —CH₂CN,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂OH, —CH₂CH₂CN, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃,—CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NH₂, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂CH₂NH₂,—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; R^(b) and R^(c) are hydrogen. In some embodiments, R^(a) is—OR⁸; and R^(b) and R^(c) are hydrogen. In some embodiments, R^(a) is—OH, —OCH₃, or —OCH₂CH₃; and R^(b) and R^(c) are hydrogen.

In some embodiments, X¹ is CH, CF or N; V is CH or N; R² and R³ arehydrogen; or R² and R³ are taken together with the carbon atom to whichthey are attached to form —C(═O)—; R^(a) is —OCH₂CH₃; R^(b) and R^(c)are hydrogen.

In some embodiments, X¹ is CH, CF or N; V is CH or N; R² and R³ arehydrogen; or R² and R³ are taken together with the carbon atom to whichthey are attached to form —C(═O)—; R^(a) is —OCH₂CH₃; R^(b) and R^(c)are hydrogen; R^(B) is as described in Table 1 and/or Table 2. R⁴ is asdescribed in Table 1 and/or Table 2.

In some embodiments, each R⁷ is independently selected from the groupconsisting of hydrogen, substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, and unsubstituted or substitutedC₁-C₆fluoroalkyl; or two R⁷ are taken together with the nitrogen atom towhich they are attached to form an unsubstituted or substituted 3- to6-membered monocyclic heterocycle. In some embodiments, each R⁷ isindependently selected from the group consisting of hydrogen, andsubstituted C₁-C₆ alkyl; or two R⁷ are taken together with the nitrogenatom to which they are attached to form an unsubstituted or substituted3- to 6-membered monocyclic heterocycle.

In some embodiments, each R⁸ is independently selected from the groupconsisting of hydrogen, substituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₃-C₆ cycloalkyl, and unsubstituted orsubstituted C₁-C₆fluoroalkyl. In some embodiments, each R⁸ isindependently selected from the group consisting of hydrogen,substituted or substituted C₁-C₆ alkyl, and unsubstituted or substitutedC₃-C₆ cycloalkyl. In some embodiments, each R⁸ is independently selectedfrom the group consisting of hydrogen and substituted or substitutedC₁-C₆ alkyl.

In some embodiments, each R⁹ is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substitutedmonocyclic heterocycle, —CN, —OH, —CO₂R⁸, —CH₂CO₂R⁸, —C(═O)N(R⁷)₂,—CH₂C(═O)N(R⁷)₂, —N(R⁷)₂, —CH₂N(R⁷)₂, —NR⁷C(═O)R⁸, or —CH₂NR⁷C(═O)R⁸. Insome embodiments, each R⁹ is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl, —CN, —OH,—CO₂R⁸, —C(═O)N(R⁷)₂, —N(R⁷)₂, or —CH₂N(R⁷)₂.

In some embodiments, each R¹⁰ is independently selected from the groupconsisting substituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, unsubstituted or substitutedC₁-C₆fluoroalkyl, and unsubstituted or substituted phenyl. In someembodiments, each R¹⁰ is independently selected from the groupconsisting substituted or substituted C₁-C₆ alkyl and unsubstituted orsubstituted phenyl.

In some embodiments, the compound of Formula (IX) has the structure ofFormula (IXa), or a pharmaceutically acceptable salt, or solvatethereof:

-   -   wherein,    -   V is CH or N.

In some embodiments, R^(B), R⁴, and X¹ are as described in Table 1and/or Table 2.

In some embodiments, compounds described herein have the followingstructure:

In some embodiments, R^(A), R^(B), R⁴, and X¹ are as described herein.

In some embodiments, R^(A), R^(B), R⁴, and X¹ are as described in Table1.

In some embodiments, compounds described herein have the followingstructure:

In some embodiments, R^(A), R^(B), R⁴, and X¹ are as described herein.

In some embodiments, R^(A), R^(B), R⁴, and X¹ are as described in Table2.

In some embodiments, compounds described herein have the followingstructure:

In some embodiments, R^(A), R^(B), R¹, R⁴, and X¹, X², X³ are asdescribed herein.

In some embodiments, R^(A), R^(B), R¹, R⁴, and X¹, X², X³ are asdescribed in Table 3.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof are chosen by one skilled in the field to providestable moieties and compounds.

Exemplary compounds of Formula (I) include the compounds described inthe following Tables:

TABLE 1

Compound No. R^(A) R^(B) X¹ R⁴ 1-1 

CH —CH₂CH₂NH₂ 1-2 

CH —CH₂CH₂NH₂ 1-3 

CH —CH₂CH₂NH₂ 1-4 

CH —CH₂CH₂NH₂ 1-5 

CH —CH₂CH₂NH₂ 1-6 

CH —CH₂CH₂NH₂ 1-7 

CH —CH₂CH₂NH₂ 1-8 

CH —CH₂CH₂NH₂ 1-9 

CH —CH₂CH₂NH₂ 1-10 

CH —CH₂CH₂NH₂ 1-11 

CH —CH₂CH₂NH₂ 1-12 

CH —CH₂CH₂NH₂ 1-13 

CH —CH₂CH₂NH₂ 1-14 

CH —CH₂CH₂NH₂ 1-15 

CH —CH₂CH₂NH₂ 1-16 

CH —CH₂CH₂NH₂ 1-17 

CH —CH₂CH₂NH₂ 1-18 

CH —CH₂CH₂NH₂ 1-19 

CH —CH₂CH₂NH₂ 1-20 

CH —CH₂CH₂NH₂ 1-21 

CH —CH₂CH₂NH₂ 1-22 

CH —CH₂CH₂NH₂ 1-23 

CH —CH₂(CH₂)₂NH₂ 1-24 

CH —CH₂(CH₂)₂NH₂ 1-25 

CH —CH₂CH₂NH₂ 1-26 

CH —CH₂CH₂NH₂ 1-27 

CH —CH₂CH₂NH₂ 1-28 

CH —CH₂CH₂NH₂ 1-29 

CH —CH₂CH₂NH₂ 1-30 

CH —CH₂CH₂NH₂ 1-31 

CH —CH₂CH₂NH₂ 1-32 

CH —CH₂CH₂NH₂ 1-33 

CH —CH₂CH₂NH₂ 1-34 

CH —CH₂CH₂NH₂ 1-35 

CH —CH₂CH₂NH₂ 1-36 

CH —CH₂CH₂NH₂ 1-37 

CH —CH₂CH₂NH₂ 1-38 

CH —CH₂CH₂NH₂ 1-39 

CH —CH₂CH₂NH₂ 1-40 

CH —CH₂CH₂NH₂ 1-41 

CH —CH₂CH₂NH₂ 1-42 

CH —CH₂CH₂NH₂ 1-43 

CH —CH₂CH₂NH₂ 1-44 

CH —CH₂CH₂NH₂ 1-45 

CH

1-46 

CH

1-47 

CH

1-48 

CH

1-49 

CH

1-50 

CH —CH₂CH₂NH₂ 1-51 

CH —CH₂CH₂NH₂ 1-52 

CH —CH₂CH₂NH₂ 1-53 

CH —CH₂CH₂NH₂ 1-54 

CH —CH₂CH₂NH₂ 1-55 

CH —CH₂CH₂NH₂ 1-56 

CH —CH₂CH₂NH₂ 1-57 

CH —CH₂CH₂NH₂ 1-58 

CH —CH₂CH₂NH₂ 1-59 

CH —CH₂CH₂NH₂ 1-60 

CH —CH₂CH₂NH₂ 1-61 

CH —CH₂CH₂NH₂ 1-62 

CH —CH₂CH₂NH₂ 1-63 

CH —CH₂CH₂NH₂ 1-64 

CH

1-65 

CH

1-66 

CH

1-67 

CH —CH₂CH₂NH₂ 1-68 

CH —CH₂CH₂NH₂ 1-69 

CF —CH₂CH₂NH₂ 1-70 

CH

1-71 

CH —CH₂CH₂NH₂ 1-72 

CF

1-73 

CF

1-74 

CH —CH₂CH₂NH₂ 1-75 

CH —CH₂CH₂NH₂ 1-76 

CH —CH₂CH₂NH₂ 1-77 

CH —CH₂CH₂NH₂ 1-78 

CH —CH₂CH₂NH₂ 1-79 

CH —CH₂CH₂NH₂ 1-80 

CH —CH₂CH₂NH₂ 1-81 

CH —CH₂CH₂NH₂ 1-82 

CH

1-83 

CH

1-84 

CH

1-85 

CH —CH₂CH₂NH₂ 1-86 

CH —CH₂CH₂NH₂ 1-87 

CH —CH₂CH₂NH₂ 1-88 

CH —CH₂CH₂NH₂ 1-89 

CH —CH₂CH₂NH₂ 1-90 

CH

1-91 

CH

1-92 

CH

1-93 

CH

1-94 

CH

1-95 

CF

1-96 

CF

1-97 

CH

1-98 

CH

1-99 

CH

1-100

CH

1-101

CH

1-102

CH

1-103

CH

1-104

CH —CH₂CH₂NH₂ 1-105

CH —CH₂CH₂NH₂ 1-106

CH —CH₂CH₂NH₂ 1-107

CH —CH₂CH₂NH₂ 1-108

CH

1-109

CH

1-110

CF

1-111

CF

1-112

CF

1-113

CF

1-114

CF

1-115

CH

1-116

CF

1-117

CH —CH₂CH₂NH₂ 1-118

CH —CH₂CH₂NH₂ 1-119

CH —CH₂CH₂NH₂ 1-120

CH —CH₂CH₂NH₂ 1-121

CF

1-122

CF

1-123

CF

1-124

CF

1-125

CH

1-126

CH —CH₂CH₂NH₂ 1-127

CH —CH₂CH₂NH₂ 1-128

CH

1-129

CH

1-130

CH

1-131

CH

1-132

CH

1-133

CH

1-134

CH

1-135

N

1-136

N

1-137

N

1-138

CH

1-139

CH

1-140

CF

1-141

CF

1-142

CH

1-143

CH

1-144

CH

1-145

CH —CH₂CH₂NH₂ 1-146

CH —CH₂CH₂NH₂ 1-147

CH

1-148

CH

1-149

N

1-150

N

1-151

N

1-152

N

1-153

CF

1-154

CF

1-155

CF

1-156

CF

1-157

CF

1-158

N

1-159

CH —CH₂CH₂NH₂ 1-160

CH —CH₂CH₂NH₂ 1-161

CH

1-162

CH

1-163

CF

1-164

CF

1-165

CF

1-166

CF

1-167

N

1-168

CF

1-169

N

1-170

CF

1-171

N

1-172

N

1-173

CF

1-174

CF

1-175

CF

1-176

CF

1-177

CF

1-178

CF

1-179

CF

1-180

CF

1-181

N

1-182

CF

1-183

CF

1-184

CF

1-185

N

1-186

CF

1-187

N

1-188

CF

1-189

CF

1-190

CF

1-191

CH

1-192

CH

1-193

CH

1-194

N

1-195

N

1-196

N

1-197

CF

1-198

CF

1-199

CF

1-200

CF

1-201

CF

1-202

CF

1-203

CF

1-204

CF

1-205

N

1-206

N

1-207

N

1-208

N

1-209

N

1-210

N

1-211

N

1-212

N

1-213

N

1-214

N

1-215

N

1-216

CH

1-217

CF

1-218

N

1-219

CF

1-220

N

1-221

N

1-222

N

1-223

N

1-224

N

1-225

N

1-226

N

1-227

N

1-228

CH

1-229

CF

1-230

N

1-231

N

1-232

N

1-233

N

1-234

N

1-235

N

1-236

N

1-237

N

1-238

N

1-239

N

1-240

N

1-241

N

1-242

N

1-243

N

1-244

N

1-245

N

1-246

N

1-247

N

1-248

N

1-249

N

1-250

N

1-251

CF

1-252

CF

1-253

N

1-254

N

1-255

N

1-256

N

1-257

N

1-258

N

1-259

N

1-260

N

1-261

N

1-262

N

1-263

N

1-264

N

1-265

N

1-266

N

1-267

N

1-268

N

1-269

N

1-270

CF

1-271

CF

1-272

N

1-273

N

1-274

N

1-275

N

1-276

N

1-277

N

1-278

N

1-279

N

1-280

N

1-281

N

1-282

N

1-283

N

1-284

N

1-285

N

1-286

N

1-287

N

1-288

N

1-289

N

1-290

N

1-291

N

1-292

N

1-293

N

1-294

N

1-295

N

1-296

N

1-297

N

1-298

N

1-299

N

1-300

N

1-301

N

1-302

N

1-303

N

1-304

N

1-305

N

1-306

N

1-307

N

1-308

N

1-309

N

1-310

N

1-311

N

1-312

N

1-313

N

1-314

N

1-315

N

1-316

N

1-317

N

1-318

N

1-319

N

1-320

N

1-321

N

1-322

N

1-323

N

1-324

N

1-325

N

1-326

N

1-327

N

1-328

N

1-329

N

1-330

N

1-331

N

1-332

N

1-333

N

1-334

N

1-335

N

1-336

N

1-337

N

1-338

N

1-339

N

1-340

N

1-341

N

1-342

N

1-343

N

1-344

N

1-345

N

1-346

N

1-347

N

1-348

N

1-349

N

1-350

N

1-351

N

1-352

N

1-353

N

1-354

N

1-355

N

1-356

N

1-357

N

1-358

N

1-359

N

1-360

N

1-361

N

1-362

N

1-363

N

1-364

N

1-365

N

1-366

N

1-367

N

1-368

N

1-369

N

1-370

N

1-371

N

1-372

N

1-373

N

1-374

N

1-375

N

1-376

N

1-377

N

1-378

N

1-379

N

1-380

N

1-381

N

1-382

N

1-383

N

1-384

N

1-385

N

1-386

N

1-387

N

1-388

N

1-389

N

1-390

N

1-391

N

1-392

N

1-393

N

1-394

N

1-395

N

1-396

N

1-397

N

1-398

N

1-399

N

1-400

N

1-401

N

1-402

N

1-403

N

1-404

N

1-405

N

1-406

N

1-407

N

1-408

N

1-409

N

1-410

N

1-411

N

1-412

N

1-413

N

1-414

N

1-415

N

1-416

N

1-417

N

1-418

N

1-419

N

1-420

N

1-421

N

1-422

N

1-423

N

1-424

N

1-425

N

1-426

N

1-427

N

1-428

N

1-429

N

1-430

N

1-431

N

1-432

N

1-433

N

1-434

N

1-435

N

1-436

N

1-437

N

1-438

N

1-439

N

* absolute stereochemistry not determined

Compounds in Table 1 are named:

-   1-1:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide;-   1-2:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methoxy-[1,1′-biphenyl]-3-carboxamide;-   1-3:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-4:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-fluoro-[1,1′-biphenyl]-3-carboxamide;-   1-5:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethyl-[1,1′-biphenyl]-3-carboxamide;-   1-6:    N-(2-aminoethyl)-2′-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-carboxamide;-   1-7:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyano-[1,1′-biphenyl]-3-carboxamide;-   1-8:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methyl-[1,1′-biphenyl]-3-carboxamide;-   1-9:    N-(2-aminoethyl)-2′-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3′-fluoro-[1,1′-biphenyl]-3-carboxamide;-   1-10:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-11:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propoxy-[1,1′-biphenyl]-3-carboxamide;-   1-12:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-(propan-2-yloxy)-[1,1′-biphenyl]-3-carboxamide;-   1-13:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-hydroxy-[1,1′-biphenyl]-3-carboxamide;-   1-14:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxamide;-   1-15:    (R)—N-(2-aminoethyl)-4-(4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-16:    (R)—N-(2-aminoethyl)-4-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-2′-(methoxymethyl)-[1,1′-biphenyl]-3-carboxamide;-   1-17:    (R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-18:    (R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-methyl-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-19: methyl    (R)-3′-((2-aminoethyl)carbamoyl)-4′-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-[1,1′-biphenyl]-2-carboxylate;-   1-20:    (R)—N3′-(2-aminoethyl)-4′-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2-methyl-[1,1′-biphenyl]-2,3′-dicarboxamide;-   1-21:    (R)—N3′-(2-aminoethyl)-4′-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-N2,N2-dimethyl-[1,1′-biphenyl]-2,3′-dicarboxamide;-   1-22:    N-(2-aminoethyl)-2′-(aminomethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-carboxamide;-   1-23:    N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-24:    N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-25:    N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-26:    N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-3′-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-27:    N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-3-fluoro-5-methyl-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   1-28:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propyl-[1,1′-biphenyl]-3-carboxamide;-   1-29:    N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-4′-propyl-[1,1′-biphenyl]-3-carboxamide;-   1-30:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-2-yl)benzamide;-   1-31:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(pyridin-3-yl)benzamide;-   1-32:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-2-yl)benzamide;-   1-33:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(3-ethoxypyridin-4-yl)benzamide;-   1-34:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-35:    N-(2-aminoethyl)-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4-ethoxypyridin-3-yl)benzamide;-   1-36:    N-(2-aminoethyl)-2-[(2R)-4-[4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-37:    N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-38:    N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-39:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyridin-4-yl)benzoyl]piperazin-1-yl]benzamide;-   1-40:    N-(2-aminoethyl)-2-[(2R)-4-{2-[(3R)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-41:    N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(aminomethyl)pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-42:    N-(2-aminoethyl)-2-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-43:    N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-44:    N-(2-aminoethyl)-2-[(2R)-4-[4′-(aminomethyl)-3-fluoro-5-methyl-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-45:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-46:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide;-   1-47:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-48:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide;-   1-49:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide;-   1-50:    N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-51:    N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-52:    N-(2-aminoethyl)-2-[(2R)-4-[2-(4-aminopiperidin-1-yl)-4-chlorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-53:    N-(2-aminoethyl)-2-[(2R)-4-(3,5-dichloropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-54:    N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methoxybenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-55:    N-(2-aminoethyl)-2-[(2R)-4-(2-chloro-4-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-56:    N-(2-aminoethyl)-2-[(2R)-4-{4-[3-(aminomethyl)pyrrolidin-1-yl]-2-fluorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-57:    N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-58:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide;-   1-59:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide;-   1-60:    N-(2-aminoethyl)-2-[(2R)-4-(2,4-dimethylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-61:    N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(pyrrolidin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-62:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]benzamide;-   1-63:    N-(2-aminoethyl)-2-[(2R)-4-(2-cyclopropylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-64:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-2-yl)methyl]benzamide;-   1-65:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-3-yl)methyl]benzamide;-   1-66:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(pyridin-4-yl)methyl]benzamide;-   1-67:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]benzamide;-   1-68:    N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-69:    N-(2-aminoethyl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-70:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(pyridin-4-yl)benzamide;-   1-71:    N-(2-aminoethyl)-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-methoxypyridin-3-yl)benzamide;-   1-72:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-73:    6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-74:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(piperidin-4-yl)benzoyl]piperazin-1-yl]benzamide;-   1-75:    N-(2-aminoethyl)-2-[(2R)-4-[2-(6-aminopyridin-3-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-76:    N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-77:    N-(2-aminoethyl)-2-[(2R)-4-(2,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-78:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methylbenzoyl)piperazin-1-yl]benzamide;-   1-79:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(4-fluoro-2-methoxybenzoyl)piperazin-1-yl]benzamide;-   1-80:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-(2-methoxy-4-methylbenzoyl)piperazin-1-yl]benzamide;-   1-81:    N-(2-aminoethyl)-2-[(2R)-4-(4-tert-butylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-82:    2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-83:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-5-yl)methyl]benzamide;-   1-84:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-5-yl)ethyl]benzamide;-   1-85:    N-(2-aminoethyl)-2-[(2R)-4-[2-(2-aminopyridin-4-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-86:    N-(2-aminoethyl)-2-[(2R)-4-(4,6-dimethylpyridine-3-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-87:    N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-88:    N-(2-aminoethyl)-2-[(2R)-4-(4-cyclopropyl-2-methylbenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-89:    N-(2-aminoethyl)-2-[(2R)-4-(3-chloro-5-fluoropyridine-2-carbonyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-90:    2-[(2R)-4-[4-chloro-2-(piperazin-1-yl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-91:    2-[(2R)-4-[4-chloro-2-(dimethylamino)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-92:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-pyrrolidin-3-yl]benzamide;-   1-93:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-imidazol-2-yl)ethyl]benzamide;-   1-94:    5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-methyl-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-95:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-96:    6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-97:    N-{[(2S)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-98:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-pyrrolidin-2-yl]methyl}benzamide;-   1-99:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide;-   1-100:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3S)-piperidin-3-yl]benzamide;-   1-101:    5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{4-fluoro-2-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-102:    N-{[(2R)-azetidin-2-yl]methyl}-2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-103:    5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-fluoro-4-[(3S)-3-(methylamino)pyrrolidin-1-yl]benzoyl}piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-104:    N-(2-aminoethyl)-2-[(2R)-4-{2-[3-(aminomethyl)pyrrolidin-1-yl]-4-methylbenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-105:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(morpholin-4-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide;-   1-106:    N-(2-aminoethyl)-2-[(2R)-4-[3-(dimethylamino)-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-107:    N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-108:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide;-   1-109:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2S)-morpholin-2-yl]methyl}benzamide;-   1-110:    6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-111:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-112:    N-{[(2S)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-113:    6-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-114:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-115:    2-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-116:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide;-   1-117:    N-(2-aminoethyl)-2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-118:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-fluoro-3-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]benzamide;-   1-119:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(methylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide;-   1-120:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide;-   1-121:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-122:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-123:    N-{[(2R)-azetidin-2-yl]methyl}-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-124:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2R)-pyrrolidin-2-yl]methyl}benzamide;-   1-125:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-126:    2-[(2R)-4-[2-amino-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide;-   1-127:    N-(2-aminoethyl)-2-[(2R)-4-[6-(dimethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-128:    2-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide;-   1-129:    N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-imidazol-1-yl)benzoyl]piperazin-1-yl]benzamide;-   1-130:    N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrrol-1-yl)benzoyl]piperazin-1-yl]benzamide;-   1-131:    N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(1H-pyrazol-1-yl)benzoyl]piperazin-1-yl]benzamide;-   1-132:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(1H-imidazol-2-yl)methyl]benzamide;-   1-133:    5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[5-(trifluoromethyl)pyridine-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-134:    2-[(2R)-4-[3-chloro-5-(trifluoromethyl)pyridine-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-135:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-136:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-137:    2′-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-138:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(3S)-morpholin-3-yl]methyl}benzamide;-   1-139:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(1H-1,2,4-triazol-1-yl)ethyl]benzamide;-   1-140:    6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide;-   1-141:    6-[(2R)-4-(4-chloro-2-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(1H-imidazol-2-yl)ethyl]benzamide;-   1-142:    2-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-143:    5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-144:    2-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-145:    2-[(2R)-4-[6-amino-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)benzamide;-   1-146:    N-(2-aminoethyl)-2-[(2R)-4-[4-(dimethylamino)-6-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-147:    2-[(2R)-4-[2-(dimethylamino)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-148:    2-[(2R)-4-[2-(3-aminoazetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-149:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide;-   1-150:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-151:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-152:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-153:    6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-154:    6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-155:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-156:    6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-157:    6-[(2R)-4-[2-cyano-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-158:    5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-159:    N-(2-aminoethyl)-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]benzamide;-   1-160:    N-(2-aminoethyl)-2-[(2R)-4-[2-(dimethylamino)-6-methylpyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-161:    2-[(2R)-4-[2-(azetidin-1-yl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)benzamide;-   1-162:    N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(pyrrolidin-1-yl)benzoyl]piperazin-1-yl]benzamide;-   1-163:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-(methylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-164:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-165:    6-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-166:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[2-methoxy-6-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-167:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-168:    N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;-   1-169:    N-[2-(dimethylamino)ethyl]-2′-ethoxy-5-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-170:    N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;-   1-171:    5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-172:    5-[(2R)-4-(2-carbamoyl-4-chlorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-173:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-174:    N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;-   1-175:    6-[(2R)-4-[4-cyano-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-176:    6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-177:    6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-178:    6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-179:    6-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-180:    6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-181:    2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-182:    N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;-   1-183:    6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-184:    6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-185:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methyl-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-186:    6-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-187:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-188:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-189:    6-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-190:    6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-191:    N-[2-(dimethylamino)ethyl]-5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-{2-[ethyl(methyl)amino]-4-fluorobenzoyl}piperazin-1-yl]benzamide;-   1-192:    2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(4,6-dimethoxypyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide;-   1-193:    2-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-5-(6-methoxy-4-oxo-1,4-dihydropyrimidin-5-yl)-N-[2-(methylamino)ethyl]benzamide;-   1-194:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethyl-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-195:    5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-196:    5-[(2R)-4-(2-chloro-4-ethoxybenzoyl)-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-197:    6-[(2R)-4-{4-chloro-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]benzoyl}-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-198:    N-(azetidin-3-yl)-6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-199:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide;-   1-200:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-pyrrolidin-3-yl]benzamide;-   1-201:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[(3S)-1-methylpyrrolidin-3-yl]benzamide;-   1-202:    N-(azetidin-3-yl)-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluorobenzamide;-   1-203:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[4-methoxy-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-2-fluoro-N-(1-methylazetidin-3-yl)benzamide;-   1-204:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-(1-methylazetidin-3-yl)benzamide;-   1-205:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethyl-[2,3′-bipyridine]-6-carboxamide;-   1-206:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-207:    N-[2-(dimethylamino)ethyl]-2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-208:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[2-(methylamino)ethyl]pyridine-2-carboxamide;-   1-209:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-210:    5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-211:    N-(azetidin-3-yl)-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-212:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-213:    5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-214:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-215:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide.    1-216:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-(1-methylazetidin-3-yl)benzamide;-   1-217:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(4-ethoxypyrimidin-5-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-218:    5-[(2R)-4-(2-chloro-4-cyclopropoxybenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-219:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(4,5-dihydro-1H-imidazol-2-yl)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide;-   1-220:    N-(azetidin-3-yl)-3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxamide;-   1-221:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide.    1-222:    N-[(azetidin-3-yl)methyl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-223:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-224:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[2-(1H-imidazol-2-yl)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-225:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-(ethylamino)-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-226:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-227:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-228:    2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-{[(2R)-1-methylazetidin-2-yl]methyl}benzamide;-   1-229:    6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-{[(2S)-1-methylazetidin-2-yl]methyl}benzamide.    1-230:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-231:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-232:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-233:    2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-234:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(1-methyl-1H-imidazol-2-yl)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-235:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopropanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-236:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-237:    3-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-238:    5-[(2R)-4-(adamantane-2-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-239:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-240:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-241:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-242:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-243:    2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-244:    N-{[(2S)-azetidin-2-yl]methyl}-2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-245:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-246:    5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2′-methoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-247:    5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2′-methoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-248:    5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-249:    2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-250:    2′-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclobutanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-251:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-252:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[trans-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   1-253:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-254:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-255:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-256:    N-{[(2S)-azetidin-2-yl]methyl}-2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-257:    2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-258:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-259:    5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-260:    5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-261:    5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-262:    5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-263:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-264:    2′-ethoxy-5-[(2R)-2-ethyl-4-(1-ethylcyclopentanecarbonyl)piperazin-1-yl]-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-265:    5-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-266:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-267:    5-[(2R)-4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-268:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-269:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-270:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide;-   1-271:    3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-2-fluoro-N-[(3R)-pyrrolidin-3-yl]benzamide;-   1-272:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(3-ethoxypyrazin-2-yl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-273:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-274:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-275:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-276:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-277:    5-[(2R)-4-(4-chloro-2-cyanobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-278:    5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-279:    5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-280:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-281:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-282:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.2]octane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-283:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-284:    2′-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-285:    2′-ethoxy-5-[(2R)-2-ethyl-4-(3,5,7-trifluoroadamantane-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-286:    2′-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-287:    3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-288:    3-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-289:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoropyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-290:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-291:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-292:    3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-293:    3-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-294:    2′-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-295:    5-[(2R)-4-[1-(difluoromethyl)-3,3-difluorocyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-296:    2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-N-[(3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-297:    2′-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-298:    5-[(2R)-4-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-299:    2′-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-300:    2′-ethoxy-5-[(2R)-2-ethyl-4-[cis-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-301:    2′-ethoxy-5-[(2R)-2-ethyl-4-[trans-3-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-302:    2′-ethoxy-5-[(2R)-2-ethyl-4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-303:    5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-304:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-305:    3-[(2R)-4-(2-tert-butylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-306:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-307:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-308:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1,2,2,3-tetramethylcyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-309: 1,1,1-trifluoro-2-methylpropan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-310:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2R)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-311:    5-[(2R)-4-(2-cyclopropylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-312: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-313:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-314:    5-[(2R)-4-{7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl}-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-315:    3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-316:    3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-317:    5-[(2R)-4-(2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-318:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoroazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-319:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-fluoro-1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-320:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-321:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-322:    2′-ethoxy-5-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-323:    5-[(2R)-4-(2,2-diethylpyrrolidine-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-324:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-pyrrolidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-325:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-pyrrolidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-326:    2′-ethoxy-5-[(2R)-2-ethyl-4-[2-methyl-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-327:    N-{[(2R)-azetidin-2-yl]methyl}-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-328:    5-[(2R)-4-[1-(2,2-difluoroethyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-329:    N-{[(2S)-azetidin-2-yl]methyl}-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-330:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-331:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-332:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylpyrrolidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-333:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-{[(2R)-1-methylpyrrolidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-334:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3-methoxy-1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-335:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-336:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[cis-4-(trifluoromethyl)cyclohexanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-337:    N-[2-(azetidin-1-yl)ethyl]-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-338: 1-(trifluoromethyl)cyclobutyl    (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate;-   1-339:    2′-ethoxy-5-[(2R)-2-ethyl-4-[2-(trifluoromethyl)bicyclo[2.2.1]heptane-2-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-340:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide;-   1-341:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-342:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-343:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-344:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-345:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-phenylpyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-346:    5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-347:    5-[(2R)-4-(5-chloro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-348: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-[6-(2-ethoxyphenyl)-2-{[(3R)-pyrrolidin-3-yl]carbamoyl}pyridin-3-yl]-3-ethylpiperazine-1-carboxylate;-   1-349:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-350:    2′-ethoxy-5-[(2R)-2-ethyl-4-(7-fluoro-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-351: (1R)-2,2,2-trifluoro-1-phenylethyl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-352:    2′-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclopentanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-353:    2′-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-354:    5-[(2R)-4-[2,2-difluoro-7,7-dimethylbicyclo[2.2.1]heptane-1-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-355:    3-[(2R)-4-[(2S)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-356:    3-[(2R)-4-[(2R)-2-tert-butylpyrrolidine-1-carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]pyridine-2-carboxamide;-   1-357:    5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(3-fluoroazetidin-1-yl)ethyl]-[2,3′-bipyridine]-6-carboxamide;-   1-358:    2′-ethoxy-5-[(2R)-2-ethyl-4-(1-phenylcyclobutanecarbonyl)piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-359:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(2,2,2-trifluoroethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-360:    2′-ethoxy-5-[(2R)-2-ethyl-4-(7-methyl-2,3-dihydro-1H-indole-1-carbonyl)piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-361:    2′-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-362:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]pyridine-2-carboxamide;-   1-363:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-364:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-365:    5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-366: (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-367: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-368:    2′-ethoxy-5-[(2R)-2-ethyl-4-[5-(trifluoromethyl)thiophene-2-carbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-369: 1,1,1,3,3,3-hexafluoropropan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-370: 3-(trifluoromethyl)pentan-3-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-371:    5-[(2R)-4-[1-(2,4-difluorophenyl)cyclobutanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-372:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-373:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-374:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-375:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-376: 1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-377: (1S)-2,2,2-trifluoro-1-phenylethyl    (3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-378:    5-[(2R)-4-(2,5-dichlorothiophene-3-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-379:    2′-ethoxy-5-[(2R)-2-ethyl-4-[3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-380:    5-[(2R)-4-(3,5-dichlorothiophene-2-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-381:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(3-fluorophenyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-382:    5-[(2R)-4-(7-chloro-2,3-dihydro-1H-indene-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-383:    5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-384: 1-phenylcyclobutyl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-385:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-386:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2R)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-387:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}pyridine-2-carboxamide;-   1-388:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-389:    2′-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-390:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-391:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-{[(2S)-1-methylazetidin-2-yl]methyl}-[2,3′-bipyridine]-6-carboxamide;-   1-392: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;    or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-393:    3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-394:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-395:    2′-ethoxy-5-[(2R)-2-ethyl-4-[4-(trifluoromethyl)bicyclo[2.2.1]heptane-1-carbonyl]piperazin-1-yl]-N-[(1-methylazetidin-3-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-396: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;    or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(2′-ethoxy-6-{[(1-methylazetidin-3-yl)methyl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-397: 1-ethylcyclopentyl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-398:    N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamide;-   1-399:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-400:    N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-401:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-402:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-403: (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;    or (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl    (3R)-4-(6-{[(3S)-1-azabicyclo[2.2.2]octan-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-404:    5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-405:    N-{1-azabicyclo[2.2.1]heptan-4-yl}-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-406:    (2R)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-407:    (2S)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-408: 2,2-dimethyl-1-phenylpropyl    (3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate;-   1-409:    5-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-410:    N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide;-   1-411:    N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-412:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-413:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(2-fluoropropan-2-yl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-414:    3-[(2R)-4-(7-cyano-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-415:    2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl]-[2,3′-bipyridine]-6-carboxamide;-   1-416:    5-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-417:    3-[(2R)-4-[1-(difluoromethyl)cyclopentanecarbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-418:    2′-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-2,3-dihydro-1H-indole-1-carbonyl]piperazin-1-yl]-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-419:    5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-420:    5-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-421:    3-[(2R)-4-(7-chloro-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-422:    5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide;-   1-423:    5-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-424:    3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-(1-methylazetidin-3-yl)pyridine-2-carboxamide;-   1-425:    5-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-426:    3-[(2R)-4-(7-cyano-5-fluoro-2,3-dihydro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-427:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-428:    5-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-429:    5-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-430:    3-[(2R)-4-(7-chloro-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-431:    3-[(2R)-4-(7-chloro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-432:    3-[(2R)-4-(7-cyano-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-433:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-434:    2′-ethoxy-5-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-435:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)piperidine-1-carbonyl]piperazin-1-yl]-N-[(3S)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-436:    2′-ethoxy-5-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1l-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;-   1-437:    6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[7-(trifluoromethyl)-1H-indole-1l-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide;-   1-438:    5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1l-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide;    and-   1-439:    3-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1l-carbonyl)-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide.

TABLE 2

Compound No. R^(A) R^(B) X¹ R⁴ 2-1 

CH

2-2 

CH

2-3 

CH H 2-4 

CH H 2-5 

CH H 2-6 

CH H 2-7 

CH H 2-8 

CH H 2-9 

CH H 2-10

CH H 2-11

CF H 2-12

N H 2-13

N H 2-14

N H 2-15

N H 2-16

N —CH₃ 2-17

N H 2-18

CF H 2-19

N H 2-20

N H 2-21

CH

2-22

CH H 2-23

CH H 2-24

CH H 2-25

N H 2-26

CH H 2-27

CH H 2-28

CH H 2-29

CH H 2-30

N H 2-31

N H

Compounds in Table 2 are named:

-   2-1:    2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-ol;-   2-2:    (2S)-1-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]propan-2-ol;-   2-3:    1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methoxy-[1,1′-biphenyl]-3-yl}methanamine;-   2-4:    1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl}methanamine;-   2-5:    1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propoxy-[1,1′-biphenyl]-3-yl}methanamine;-   2-6:    2-{[3′-(aminomethyl)-4′-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-2-yl]oxy}ethan-1-ol;-   2-7:    2-{[3′-(aminomethyl)-4′-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1′-biphenyl]-2-yl]oxy}ethan-1-ol;-   2-8:    [3′-(aminomethyl)-4′-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-2-yl]methanol;-   2-9:    1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine;-   2-10:    1-{2-[(2R)-4-[4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}methanamine;-   2-11:    1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine;-   2-12:    1-{3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridin-2-yl}methanamine;-   2-13:    1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine;-   2-14:    1-{5-[(2R)-4-(2-chloro-4-methylbenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine;-   2-15:    1-{5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine;-   2-16:    ({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methyl)(methyl)amine;-   2-17:    1-{5-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine;-   2-18:    1-{6-[(2R)-4-(2-chloro-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}methanamine;-   2-19:    1-{2′-ethoxy-5-[(2R)-2-ethyl-4-(2,3,4-trifluorobenzoyl)piperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine;-   2-20:    1-{2′-ethoxy-5-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine;-   2-21:    {[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethyl-4-[4-fluoro-2-(trifluoromethyl)benzoyl]piperazin-1-yl]phenyl]methyl}[2-(methylamino)ethyl]amine;-   2-22:    13-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N-methylpyridin-2-amine;-   2-23:    3-[3-(aminomethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]phenyl]-N,N-dimethylpyridin-2-amine;-   2-24:    1-{2-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-[2-(pyrrolidin-1-yl)pyridin-3-yl]phenyl}methanamine;-   2-25:    1-{2′-ethoxy-5-[(2R)-4-[4-ethoxy-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine;-   2-26:    1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-3′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;-   2-27:    1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1′-biphenyl]-3-yl}methanamine;-   2-28:    1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-4′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;-   2-29:    1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-5′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;-   2-30:    1-{2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine;    and-   2-31:    1-{2′-ethoxy-5-[(2R)-2-ethyl-4-[6-methoxy-2-(trifluoromethyl)pyridine-3-carbonyl]piperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine.

TABLE 3

Compound No. R^(A) —L—R^(B) X¹ X² X³ R¹ R⁴ 3-1

CH CH CH H

3-2

CH CH CH H

3-3

CF CH CH (2R)—CH₂CH₃

3-4

CF CH CH (2R)—CH₂CH₃

3-5

CH CH CH (3R)—CH₂CH₃

3-6

CH CH CH (3R)—CH₃

3-7

N CH N (2R)—CH₂CH₃

3-8

N CH N (2R)—CH₂CH₃

3-9

CH N CH (2R)—CH₂CH₃

Compounds in Table 3 are named:

-   3-1:    N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide;-   3-2:    N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;-   3-3:    6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide;-   3-4:    (3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl}phenyl]-3-ethylpiperazine-1-carboxamide;-   3-5:    N-(2-aminoethyl)-2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide;-   3-6:    2-[(3R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-3-methylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]benzamide;-   3-7:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxamide;-   3-8:    3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide;    and-   3-9:    N-(2-aminoethyl)-5-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2-(2-ethoxyphenyl)pyridine-4-carboxamide.

In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial is administered to an individual without causing undesirablebiological effects or interacting in a deleterious manner with any ofthe components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a form of atherapeutically active agent that consists of a cationic form of thetherapeutically active agent in combination with a suitable anion, or inalternative embodiments, an anionic form of the therapeutically activeagent in combination with a suitable cation. Handbook of PharmaceuticalSalts: Properties, Selection and Use. International Union of Pure andApplied Chemistry, Wiley-VCH 2002. S. M. Berge, L. D. Bighley, D. C.Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth,editors, Handbook of Pharmaceutical Salts: Properties, Selection andUse, Weinheim/Ztrich:Wiley-VCH/VHCA, 2002. Pharmaceutical saltstypically are more soluble and more rapidly soluble in stomach andintestinal juices than non-ionic species and so are useful in soliddosage forms. Furthermore, because their solubility often is a functionof pH, selective dissolution in one or another part of the digestivetract is possible and this capability can be manipulated as one aspectof delayed and sustained release behaviours. Also, because thesalt-forming molecule can be in equilibrium with a neutral form, passagethrough biological membranes can be adjusted.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I) with an acid. In some embodiments,the compound of Formula (I) (i.e. free base form) is basic and isreacted with an organic acid or an inorganic acid. Inorganic acidsinclude, but are not limited to, hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.Organic acids include, but are not limited to, 1-hydroxy-2-naphthoicacid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid;2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid;acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L);benzenesulfonic acid; benzoic acid; camphoric acid (+);camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid(hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamicacid; citric acid; cyclamic acid; dodecylsulfuric acid;ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaricacid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconicacid (D); glucuronic acid (D); glutamic acid; glutaric acid;glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid;lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid(−L); malonic acid; mandelic acid (DL); methanesulfonic acid;naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinicacid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoricacid; proprionic acid; pyroglutamic acid (−L); salicylic acid; sebacicacid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L);thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

In some embodiments, a compound of Formula (I) is prepared as a chloridesalt, sulfate salt, bromide salt, mesylate salt, maleate salt, citratesalt or phosphate salt.

In some embodiments, pharmaceutically acceptable salts are obtained byreacting a compound of Formula (I) with a base. In some embodiments, thecompound of Formula (I) is acidic and is reacted with a base. In suchsituations, an acidic proton of the compound of Formula (I) is replacedby a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, oran aluminum ion. In some cases, compounds described herein coordinatewith an organic base, such as, but not limited to, ethanolamine,diethanolamine, triethanolamine, tromethamine, meglumine,N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. Inother cases, compounds described herein form salts with amino acids suchas, but not limited to, arginine, lysine, and the like. Acceptableinorganic bases used to form salts with compounds that include an acidicproton, include, but are not limited to, aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium hydroxide, lithium hydroxide, and the like. In some embodiments,the compounds provided herein are prepared as a sodium salt, calciumsalt, potassium salt, magnesium salt, meglumine salt, N-methylglucaminesalt or ammonium salt.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. In someembodiments, solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and are formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, and the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.Solvates of compounds described herein are conveniently prepared orformed during the processes described herein. In addition, the compoundsprovided herein optionally exist in unsolvated as well as solvatedforms.

The methods and formulations described herein include the use ofN-oxides (if appropriate), or pharmaceutically acceptable salts ofcompounds having the structure of Formula (I), as well as activemetabolites of these compounds having the same type of activity.

In some embodiments, sites on the organic radicals (e.g. alkyl groups,aromatic rings) of compounds of Formula (I) are susceptible to variousmetabolic reactions. Incorporation of appropriate substituents on theorganic radicals will reduce, minimize or eliminate this metabolicpathway. In specific embodiments, the appropriate substituent todecrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium, analkyl group, a haloalkyl group, or a deuteroalkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine,phosphorus, such as, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I, ¹³¹I, ³²P and ³³P. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, the compounds of Formula (I) possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. In some embodiments, the compound of Formula (I)exists in the R configuration. In some embodiments, the compound ofFormula (I) exists in the S configuration. The compounds presentedherein include all diastereomeric, individual enantiomers, atropisomers,and epimeric forms as well as the appropriate mixtures thereof. Thecompounds and methods provided herein include all cis, trans, syn, anti,entgegen (E), and zusammen (Z) isomers as well as the appropriatemixtures thereof.

Individual stereoisomers are obtained, if desired, by methods such as,stereoselective synthesis and/or the separation of stereoisomers bychiral chromatographic columns or the separation of diastereomers byeither non-chiral or chiral chromatographic columns or crystallizationand recrystallization in a proper solvent or a mixture of solvents. Incertain embodiments, compounds of Formula (I) are prepared as theirindividual stereoisomers by reacting a racemic mixture of the compoundwith an optically active resolving agent to form a pair ofdiastereoisomeric compounds/salts, separating the diastereomers andrecovering the optically pure individual enantiomers. In someembodiments, resolution of individual enantiomers is carried out usingcovalent diastereomeric derivatives of the compounds described herein.In another embodiment, diastereomers are separated byseparation/resolution techniques based upon differences in solubility.In other embodiments, separation of steroisomers is performed bychromatography or by the forming diastereomeric salts and separation byrecrystallization, or chromatography, or any combination thereof. JeanJacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates andResolutions”, John Wiley And Sons, Inc., 1981. In some embodiments,stereoisomers are obtained by stereoselective synthesis.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they are easier to administer than the parent drug. Theyare, for instance, bioavailable by oral administration whereas theparent is not. Further or alternatively, the prodrug also has improvedsolubility in pharmaceutical compositions over the parent drug. In someembodiments, the design of a prodrug increases the effective watersolubility. An example, without limitation, of a prodrug is a compounddescribed herein, which is administered as an ester (the “prodrug”) butthen is metabolically hydrolyzed to provide the active entity. A furtherexample of a prodrug is a short peptide (polyaminoacid) bonded to anacid group where the peptide is metabolized to reveal the active moiety.In certain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, N-alkyloxyacyl derivatives, quaternaryderivatives of tertiary amines, N-Mannich bases, Schiff bases, aminoacid conjugates, phosphate esters, and sulfonate esters. See for exampleDesign of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method inEnzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396;Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of DrugDesign and Development, Krosgaard-Larsen and H. Bundgaard, Ed., 1991,Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review,1992, 8, 1-38, each of which is incorporated herein by reference. Insome embodiments, a hydroxyl group in the compounds disclosed herein isused to form a prodrug, wherein the hydroxyl group is incorporated intoan acyloxyalkyl ester, alkoxycarbonyloxyalkyl ester, alkyl ester, arylester, phosphate ester, sugar ester, ether, and the like. In someembodiments, a hydroxyl group in the compounds disclosed herein is aprodrug wherein the hydroxyl is then metabolized in vivo to provide acarboxylic acid group. In some embodiments, a carboxyl group is used toprovide an ester or amide (i.e. the prodrug), which is then metabolizedin vivo to provide a carboxylic acid group. In some embodiments,compounds described herein are prepared as alkyl ester prodrugs.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I) as set forthherein are included within the scope of the claims. In some cases, someof the herein-described compounds is a prodrug for another derivative oractive compound.

In some embodiments, any one of the hydroxyl group(s), amino group(s)and/or carboxylic acid group(s) are functionalized in a suitable mannerto provide a prodrug moiety. In some embodiments, the prodrug moiety isas described above.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

Synthesis of Compounds

Compounds of Formula (I) described herein are synthesized using standardsynthetic techniques or using methods known in the art in combinationwith methods described herein.

Unless otherwise indicated, conventional methods of mass spectroscopy,NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniquesand pharmacology are employed.

Compounds are prepared using standard organic chemistry techniques suchas those described in, for example, March's Advanced Organic Chemistry,6^(th) Edition, John Wiley and Sons, Inc. Alternative reactionconditions for the synthetic transformations described herein may beemployed such as variation of solvent, reaction temperature, reactiontime, as well as different chemical reagents and other reactionconditions.

In some embodiments, compounds described herein are prepared asdescribed in Scheme A.

Compound I is obtained by heating methyl 2-fluoro-5-nitrobenzoate ormethyl 2,6-difluoro-3-nitrobenzoate with a mono-protected substitutedpiperazine in the presence of organic base such asN,N-diisopropylethylamine. An iron-catalyzed reduction of nitro groupyields an aryl amine, which is subsequently transformed to an arylbromide (II) via preparation of diazonim salt and subsequentdisplacement with Br anion under copper (I) catalysis. Compound II issubjected to organometallic coupling reaction such as Suzuki-Miyaurareaction with R^(A)B(OH)₂ or its corresponding ester and is followed bya standard hydrolysis to generate compound III. Compound IV is convertedto the intermediate V via an iron-catalyzed nitro reduction and asubsequent Sandmeyer reaction of the aniline. Alternatively, Compound Vcan be also obtained from a standard deprotection of II.

In some embodiments, compounds described herein are prepared asdescribed in Scheme B.

Compound V is converted to the intermediate VI by treating with anactivated carboxylic acid using HATU and triethylamine or an acylchloride in the presence of triethylamine or other bases. Compound VIIis prepared from the aryl bromide (VI) by organometallic couplingreactions such as Suzuki-Miyaura reaction with boronic acid R^(A)B(OH)₂or its ester or Stille coupling with R^(A)SnBu₃. The direct conversionof the carboxylic ester (VII) to the amide (VIII) is achieved by heatingit with a diamine in a polar protic solvent. Alternatively, compound VIis converted into the corresponding boronic ester intermediate (IX)which is subsequently subject to coupling reaction such asSuzuki-Miyaura reaction with an aryl halide such as R^(A)—Br and isfollowed by the conversion of the ester to the amide to yield VIII.

In some embodiments, compounds described herein are prepared asdescribed in Scheme C.

Compound III is reacted with an amine (R⁴R⁵NH) in the presence of HATUand triethylamine yielding intermediate X. Compound X is subjected toremoval of Boc group with TFA or other acid and then formation of theamide with R^(A)CO₂H, or R^(A)COCl to give XI. If R⁴ or R⁵ contains aprotecting group, then an additional deprotection step takes place toproduce XI. Alternatively, intermediate XII is obtained fromdeprotection of Ill by TFA is converted to XIII by treating withpre-activated R^(B)CO₂H. Compound XIII is utilized to produce thecorresponding amides (XI) similarly.

In some embodiments, compounds described herein are prepared asdescribed in Scheme D.

Compound II is subjected to a Suzuki coupling with boronic acidR^(B)(OH)₂ in the presence of a transition metal catalyst, yielding theintermediate (XIV). The caboxylic ester on XIV is reduced to an alcoholusing NaBH₄ followed by oxidation with 2-iodoxybenzoic acid to affordthe benzaldehyde XV which is subjected to reductive amination reactionwith an appropriate amine (R⁴R⁵NH) and a reducing agent such asNaBH(OAc)₃ to afford XVI. A subsequent Boc deprotection and then amideformation with R^(B)CO₂H yields compound XVII. If R⁴ contains aprotecting group, then an additional deprotection step takes place toproduce XVII.

In some embodiments, compounds described herein are prepared asdescribed in Scheme E.

Compound XVIII is prepared by Suzuki-Miyaura coupling reaction with aboronic acid R^(A)B(OH)₂ or Stille coupling with R^(A)SnBu₃, whichreacts with a mono-protected substituted piperazine in the presence ofan organic base such as DIEA to afford XIX. Subsequently, Boc group isremoved by an acid and the corresponding amide is formed via standardamide formation reaction with R^(B)CO₂H to afford XX. Nickel (II)catalyzed reduction of the carbonitrile produces benzyl amine analogues(XXII-B). Hydrolysis of —CN on XX with a strong inorganic base such asKOH affords the carboxylic acid intermediate (XXI), which is convertedto compound XXII-A by coupling reaction with R⁴R⁵NH. If R⁴ contains aprotecting group, then an additional deprotection step takes place toproduce XXII. Alternatively, XXII-A is prepared via 4-step synthesisstarting from XIX by first hydrolysis of cyano group to the carboxylicacid, followed by amide formation with R⁴R⁵NH to form XXIII, then Bocgroup is removed and R^(B)CO₂H or R^(B)COCl is used to obtain XXII-A. IfR⁴ contains a protecting group, then appropriate deprotection step toremove the protecting group is conducted to produce XXII. In someembodiments, compound XXII-B is prepared via an alternative pathway fromXIX as follows: cyano group is reduced by NaBH₄ in the presence ofNiCl₂. The newly formed amine is then protected by a Cbz group.Subsequently Boc group is removed, followed by amide formation withR^(B)CO₂H. Finally, Cbz group is removed by stirring in hot TFA toafford XXXII-B.

In some embodiments, compounds described herein are prepared asdescribed in Scheme F.

Heating of methyl 6-bromo-3-chloropyrazine-2-carboxylate with amono-protected substituted piperazine yields compound XXIV, which issubsequently subjected to Suzuki-Miyaura coupling reaction withR^(A)B(OH)₂ and is followed by hydrolysis of ester to acid and astandard de-Boc procedure to yield XXV. XXVI is obtained from a couplingreaction with a pre-activated R^(B)CO₂H and further reaction with R⁴R⁵NHin the presence of HATU affords XXVII. If R⁴ or R⁵ contains a protectinggroup, then an additional deprotection step takes place to produce XXI.

In some embodiments, compounds described herein are prepared asdescribed in Scheme G.

The Boc group on II is removed to yield XXVIII, which is treated withR^(B)—Cl or R^(B)—F and is followed by saponification of ester to formXXIX. Coupling reaction of XXIX with R⁴R⁵NH yields XXX, which undergoesSuzuki-Miyaura reaction with the boronic acid R^(A)B(OH)₂ to affordXXXI. An additional removal of protecting group takes place if R⁴ or R⁵contains a protecting group on XXXI.

In some embodiments, compounds described herein are prepared asdescribed in Scheme H.

The Boc group of on X is removed to form XXXII, which is reacted witharyl sulfonyl chloride in the presence of an organic base to affordXXXIII. In a similar manner, urea analogues (XXXIV) are prepared byeither reaction with an isocyanates (R^(B)NCO) or reaction R^(B)R⁷CO₂Phor reacting XXXII with triphosgene and then R^(B)R⁷NH. In addition, anefficient synthesis of carbamate derivatives (XXXV) was achieved byreacting XXXII with the CDI activated alcohols. If R⁴ contains aprotecting group, then it is removed subsequently with an appropriatecondition on XXXIII, XXXIV, or XXXV.

In some embodiments, compounds described herein are synthesized asoutlined in the Examples.

Certain Terminology

Unless otherwise stated, the following terms used in this applicationhave the definitions given below. The use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting. The section headings used herein are for organizationalpurposes only and are not to be construed as limiting the subject matterdescribed.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). By way ofexample only, a group designated as “C₁-C₆” indicates that there are oneto six carbon atoms in the moiety, i.e. groups containing 1 carbon atom,2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way ofexample only, “C₁-C₄ alkyl” indicates that there are one to four carbonatoms in the alkyl group, i.e., the alkyl group is selected from amongmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is branched or straight chain. In some embodiments, the “alkyl”group has 1 to 10 carbon atoms, i.e. a C₁-C₁₀alkyl. Whenever it appearsherein, a numerical range such as “1 to 10” refers to each integer inthe given range; e.g., “1 to 10 carbon atoms” means that the alkyl groupconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 10 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated. In some embodiments, an alkyl is a C₁-C₆alkyl. In one aspectthe alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, or t-butyl. Typical alkyl groups include, but are in no waylimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

An “alkylene” group refers refers to a divalent alkyl radical. Any ofthe above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. In someembodiments, an alkelene is a C₁-C₆alkylene. In other embodiments, analkylene is a C₁-C₄alkylene. Typical alkylene groups include, but arenot limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and thelike. In some embodiments, an alkylene is —CH₂—.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where x is0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom isreplaced by a hydroxyl. In some embodiments, a hydroxyalkyl is aC₁-C₄hydroxyalkyl. Typical hydroxyalkyl groups include, but are notlimited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, and thelike.

An “aminoalkyl” refers to an alkyl in which one hydrogen atom isreplaced by an amino. In some embodiments, aminoalkyl is aC₁-C₄aminoalkyl. Typical aminoalkyl groups include, but are not limitedto, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, and the like.

The term “alkenyl” refers to a type of alkyl group in which at least onecarbon-carbon double bond is present. In one embodiment, an alkenylgroup has the formula —C(R)═CR₂, wherein R refers to the remainingportions of the alkenyl group, which may be the same or different. Insome embodiments, R is H or an alkyl. In some embodiments, an alkenyl isselected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl,pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenylgroup include —CH═CH₂, —C(CH₃)═CH₂, —CH═CHCH₃, —C(CH₃)═CHCH₃, and—CH₂CH═CH₂.

The term “alkynyl” refers to a type of alkyl group in which at least onecarbon-carbon triple bond is present. In one embodiment, an alkenylgroup has the formula —C≡C—R, wherein R refers to the remaining portionsof the alkynyl group. In some embodiments, R is H or an alkyl. In someembodiments, an alkynyl is selected from ethynyl, propynyl, butynyl,pentynyl, hexynyl, and the like. Non-limiting examples of an alkynylgroup include —C≡CH, —C≡CCH₃ —C≡CCH₂CH₃, —CH₂C≡CH.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-, sulfur, or combinationsthereof. A heteroalkyl is attached to the rest of the molecule at acarbon atom of the heteroalkyl. In one aspect, a heteroalkyl is aC₁-C₆heteroalkyl.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer. Theterm “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl)and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups(e.g., pyridine). The term includes monocyclic or fused-ring polycyclic(i.e., rings which share adjacent pairs of carbon atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from “heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atomwhich is different from carbon. In some embodiments, a carbocycle is amonocyclic carbocycle or a bicyclic carbocycle. In some embodiments, acarbocycle is a monocyclic carbocycle. Carbocycles are non-aromatic oraromatic. Non-aromatice carbocyles are saturated or partiallyunsaturated. In some embodiments, a carbocycle is a bicyclic carbocycle.In some embodiments, at least one of the two rings of a bicycliccarbocycle is aromatic. In some embodiments, both rings of a bicycliccarbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. In one aspect, aryl isphenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In someembodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, ortetrahyodronaphthyl. In some embodiments, an aryl is a C₆-C₁₀aryl.Depending on the structure, an aryl group is a monoradical or adiradical (i.e., an arylene group).

The term “cycloalkyl” refers to a monocyclic, bicyclic or polycyclicaliphatic, non-aromatic radical, wherein each of the atoms forming thering (i.e. skeletal atoms) is a carbon atom. In some embodiments,cycloalkyls are spirocyclic or bridged compounds. In some embodiments,cycloalkyls are optionally fused with an aromatic ring, and the point ofattachment is at a carbon that is not an aromatic ring carbon atom.Cycloalkyl groups include groups having from 3 to 10 ring atoms. In someembodiments, cycloalkyl groups are selected from among cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, norbornenyl,bicycle[1.1.1]pentyl, adamantyl, norbornyl, norbornenyl, decalinyl, or7,7-dimethyl-bicyclo[2.2.1]heptanyl. In some embodiments, a cycloalkylis a C₃-C₆cycloalkyl. In some embodiments, a cycloalkyl is a monocycliccycloalkyl. Monocyclic cycloalkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl,norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro,chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, orbromo.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆fluoroalkyl.

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings containing one tofour heteroatoms in the ring(s), where each heteroatom in the ring(s) isselected from O, S and N, wherein each heterocyclic group has from 3 to10 atoms in its ring system, and with the proviso that any ring does notcontain two adjacent O or S atoms. Non-aromatic heterocyclic groups(also known as heterocycloalkyls) include rings having 3 to 10 atoms inits ring system and aromatic heterocyclic groups include rings having 5to 10 atoms in its ring system. The heterocyclic groups includebenzo-fused ring systems. Examples of non-aromatic heterocyclic groupsare pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl,indolin-2-onyl, isoindolin-1-onyl, isoindoline-1,3-dionyl,3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl,isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl,1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups are either C-attached (or C-linked)or N-attached where such is possible. For instance, a group derived frompyrrole includes both pyrrol-1-yl (N-attached) or pyrrol-3-yl(C-attached). Further, a group derived from imidazole includesimidazol-1-yl or imidazol-3-yl (both N-attached) or imidazol-2-yl,imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groupsinclude benzo-fused ring systems. Non-aromatic heterocycles areoptionally substituted with one or two oxo (═O) moieties, such aspyrrolidin-2-one. In some embodiments, at least one of the two rings ofa bicyclic heterocycle is aromatic. In some embodiments, both rings of abicyclic heterocycle are aromatic.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude monocyclic heteroaryls and bicyclcic heteroaryls. Monocyclicheteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl,triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl,thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine,indole, benzofuran, benzothiophene, indazole, benzimidazole, purine,quinolizine, quinoline, isoquinoline, cinnoline, phthalazine,quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In someembodiments, a heteroaryl contains 0-4 N atoms in the ring. In someembodiments, a heteroaryl contains 1-4 N atoms in the ring. In someembodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl contains 1-4 Natoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments,heteroaryl is a C₁-C₉heteroaryl. In some embodiments, monocyclicheteroaryl is a C₁-C₅heteroaryl. In some embodiments, monocyclicheteroaryl is a 5-membered or 6-membered heteroaryl. In someembodiments, bicyclic heteroaryl is a C₆-C₉heteroaryl.

A “heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. In someembodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. Insome embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl,pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl,imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heterocycloalkylalso includes all ring forms of the carbohydrates, including but notlimited to the monosaccharides, the disaccharides and theoligosaccharides. In one aspect, a heterocycloalkyl is aC₂-C₁₀heterocycloalkyl. In another aspect, a heterocycloalkyl is aC₄-C₁₀heterocycloalkyl. In some embodiments, a heterocycloalkyl contains0-2 N atoms in the ring. In some embodiments, a heterocycloalkylcontains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from halogen, —CN,—NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H, —CO₂alkyl, —C(═O)NH₂,—C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(alkyl),—S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy,fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone.In some other embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(alkyl), —N(alkyl)₂, —OH, —CO₂H,—CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl,heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl,aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some other embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂,—NH(CH₃), —N(CH₃)₂, —OH, —CO₂H, —CO₂(C₁-C₄alkyl), —C(═O)NH₂,—C(═O)NH(C₁-C₄alkyl), —C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(C₁-C₄alkyl), —S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl,C₃-C₆cycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some other embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH,—CO₂H, —CO₂(C₁-C₄alkyl), —C(═O)NH₂, —C(═O)NH(C₁-C₄alkyl),—C(═O)N(C₁-C₄alkyl)₂, —S(═O)₂NH₂, —S(═O)₂NH(C₁-C₄alkyl),—S(═O)₂N(C₁-C₄alkyl)₂, C₁-C₄alkyl, C₃-C₆cycloalkyl,C₂-C₆heterocycloalkyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄alkoxy,C₁-C₄fluoroalkoxy, —SC₁-C₄alkyl, —S(═O)C₁-C₄alkyl, and—S(═O)₂C₁-C₄alkyl. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —OH, —NH(CH₃), —N(CH₃)₂,—CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In some embodiments, substitutedgroups are substituted with one or two of the preceding groups. In someembodiments, an optional substituent on an aliphatic carbon atom(acyclic or cyclic) includes oxo (═O).

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an agonist.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof compounds or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Those of skill in the art are familiar withadministration techniques that can be employed with the compounds andmethods described herein. In some embodiments, the compounds andcompositions described herein are administered orally.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered, which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result includesreduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case is optionallydetermined using techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and a co-agent, are both administered to apatient simultaneously in the form of a single entity or dosage. Theterm “non-fixed combination” means that the active ingredients, e.g. acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a co-agent, are administered to a patient as separate entitieseither simultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The terms “article of manufacture” and “kit” are used as synonyms.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Pharmaceutical Compositions

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that are used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999),herein incorporated by reference for such disclosure.

In some embodiments, the compounds described herein are administeredeither alone or in combination with pharmaceutically acceptablecarriers, excipients or diluents, in a pharmaceutical composition.Administration of the compounds and compositions described herein can beeffected by any method that enables delivery of the compounds to thesite of action. These methods include, though are not limited todelivery via enteral routes (including oral, gastric or duodenal feedingtube, rectal suppository and rectal enema), parenteral routes (injectionor infusion, including intraarterial, intracardiac, intradermal,intraduodenal, intramedullary, intramuscular, intraosseous,intraperitoneal, intrathecal, intravascular, intravenous, intravitreal,epidural and subcutaneous), inhalational, transdermal, transmucosal,sublingual, buccal and topical (including epicutaneous, dermal, enema,eye drops, ear drops, intranasal, vaginal) administration, although themost suitable route may depend upon for example the condition anddisorder of the recipient. By way of example only, compounds describedherein can be administered locally to the area in need of treatment, byfor example, local infusion during surgery, topical application such ascreams or ointments, injection, catheter, or implant. The administrationcan also be by direct injection at the site of a diseased tissue ororgan.

In some embodiments, pharmaceutical compositions suitable for oraladministration are presented as discrete units such as capsules, cachetsor tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. In some embodiments, theactive ingredient is presented as a bolus, electuary or paste.

Pharmaceutical compositions which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. In some embodiments, the tabletsare coated or scored and are formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In some embodiments, stabilizers are added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or Dragee coatings for identification or to characterizedifferent combinations of active compound doses.

In some embodiments, pharmaceutical compositions are formulated forparenteral administration by injection, e.g., by bolus injection orcontinuous infusion. Formulations for injection may be presented in unitdosage form, e.g., in ampoules or in multi-dose containers, with anadded preservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored inpowder form or in a freeze-dried (lyophilized) condition requiring onlythe addition of the sterile liquid carrier, for example, saline orsterile pyrogen-free water, immediately prior to use. Extemporaneousinjection solutions and suspensions may be prepared from sterilepowders, granules and tablets of the kind previously described.

Pharmaceutical compositions for parenteral administration includeaqueous and non-aqueous (oily) sterile injection solutions of the activecompounds which may contain antioxidants, buffers, bacteriostats andsolutes which render the formulation isotonic with the blood of theintended recipient; and aqueous and non-aqueous sterile suspensionswhich may include suspending agents and thickening agents. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

Pharmaceutical compositions may also be formulated as a depotpreparation. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may beformulated with suitable polymeric or hydrophobic materials (forexample, as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

Pharmaceutical compositions may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof the present invention externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Pharmaceutical compositions suitable for topical administration includeliquid or semi-liquid preparations suitable for penetration through theskin to the site of inflammation such as gels, liniments, lotions,creams, ointments or pastes, and drops suitable for administration tothe eye, ear or nose. The active ingredient may comprise, for topicaladministration, from 0.001% to 10% w/w, for instance from 1% to 2% byweight of the formulation.

Pharmaceutical compositions for administration by inhalation areconveniently delivered from an insufflator, nebulizer pressurized packsor other convenient means of delivering an aerosol spray. Pressurizedpacks may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Alternatively, foradministration by inhalation or insufflation, pharmaceuticalpreparations may take the form of a dry powder composition, for examplea powder mix of the compound and a suitable powder base such as lactoseor starch. The powder composition may be presented in unit dosage form,in for example, capsules, cartridges, gelatin or blister packs fromwhich the powder may be administered with the aid of an inhalator orinsufflator.

It should be understood that in addition to the ingredients particularlymentioned above, the compounds and compositions described herein mayinclude other agents conventional in the art having regard to the typeof formulation in question, for example those suitable for oraladministration may include flavoring agents.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, are used in the preparation of medicaments forthe treatment of diseases or conditions in a mammal that would benefitfrom modulation of melanocortin receptor activity. Methods for treatingany of the diseases or conditions described herein in a mammal in needof such treatment, involves administration of pharmaceuticalcompositions that include at least one compound of Formula (I) or apharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said mammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation and/or dose ranging clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in patients, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in order to prevent a return of the symptoms ofthe disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but nevertheless is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-2000 mg per day. In one embodiment,the desired dose is conveniently presented in a single dose or individed doses administered simultaneously or at appropriate intervals,for example as two, three, four or more sub-doses per day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), or a pharmaceutically acceptable salt thereof, describedherein are from about 0.01 to about 50 mg/kg per body weight. In someembodiments, the daily dosage or the amount of active in the dosage formare lower or higher than the ranges indicated herein, based on a numberof variables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), or apharmaceutically acceptable salt thereof, is: (a) systemicallyadministered to the mammal; and/or (b) administered orally to themammal; and/or (c) intravenously administered to the mammal; and/or (d)administered by injection to the mammal; and/or (e) administeredtopically to the mammal; and/or (f) administered non-systemically orlocally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce a day; or (ii) the compound is administered to the mammal multipletimes over the span of one day.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), or a pharmaceutically acceptable salt thereof,in combination with one or more other therapeutic agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant has minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, in some embodiments, the benefit experiencedby a patient is increased by administering one of the compoundsdescribed herein with another agent (which also includes a therapeuticregimen) that also has therapeutic benefit.

In one specific embodiment, a compound of Formula (I), or apharmaceutically acceptable salt thereof, is co-administered with asecond therapeutic agent, wherein the compound of Formula (I), or apharmaceutically acceptable salt thereof, and the second therapeuticagent modulate different aspects of the disease, disorder or conditionbeing treated, thereby providing a greater overall benefit thanadministration of either therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient is simply beadditive of the two therapeutic agents or the patient experiences asynergistic benefit.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds of Formula (I), or a pharmaceutically acceptable saltthereof, as well as combination therapies, are administered before,during or after the occurrence of a disease or condition, and the timingof administering the composition containing a compound varies. Thus, inone embodiment, the compounds described herein are used as aprophylactic and are administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. In another embodiment, thecompounds and compositions are administered to a subject during or assoon as possible after the onset of the symptoms. In specificembodiments, a compound described herein is administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease. In some embodiments, the length required for treatment varies,and the treatment length is adjusted to suit the specific needs of eachsubject.

Abbreviations DIEA: N,N-diisopropylethylamine;

DMSO: dimethyl sulfoxide;Pd(PPh₃)₄: tetrakis(triphenylphosphine)palladium(0)Pd(dppf)Cl₂: [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride;CuI: copper(I) iodide;TBAF: tetra-n-butylammonium fluoride;P(t-Bu)₃: tri-tert-buytlphosphine;HBF₄: tetrafluoroboric acid;DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene;Prep-HPLC: preparative high performance liquid chromatography;TFA: trifluoroacetic acid;CH₃CN, MeCN, or ACN: acetonitrile;MeOD: deuterated methanol;CDCl₃: deuterated chloroformDME: 1,2-dimethoxyethane;

DMF: N,N-dimethylformamide

DCM: dichloromethaneH₂O: water;KOAc: potassium acetate;NaOAc: sodium acetate;Cs₂CO₃: cesium carbonateP-TsOH: p-toluenesulfonic acid;NaNO₂: sodium nitrite;THF: tetrahydrofuran;

NBS: N-bromosuccinimide;

Br₂: bromine;AgF: silver fluoride;LiAlH₄: lithium aluminium hydride;IBX: 2-iodoxybenzoic acid;TEA: trimethylamine;DMAP: N,N-dimethylpyridine-4-amineHOBT: hydroxybenzotriazole;EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;Pd(PPh₃)₂Cl₂: bis(triphenylphosphine)palladium(II) dichloride;PdAMphos or Pd (amphos)Cl₂ or:bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);Pd(DTBPF)Cl₂:[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);cc: column chromatographyrt: room temperature;h: hour or hours.

EXAMPLES

The following examples are provided for illustrative purposes only andnot to limit the scope of the claims provided herein.

Synthesis of Compounds Example 1:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide(Compound 1-1)

Step 1-1, preparation of tert-butyl(3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate:into a 40-mL round bottom flask, was placed methyl2-fluoro-5-nitrobenzoate (2.2 g, 0.01 mmol, 1.2 eq.), tert-butyl(3R)-3-ethylpiperazine-1-carboxylate (2.0 g, 9.33 mmol), TEA (2.8 g,0.03 mmol, 3.0 eq.) and DMSO (20 mL). The resulting solution was stirredat 100° C. for 2 h and cooled to rt. The reaction was diluted with water(50 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine (2×50 mL), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:3). 3.3g (90%) of the title compound as a brown oil. LCMS (M+H)⁺: 394.2.

Step 1-2, preparation of methyl2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate: a solution of tert-butyl(3R)-3-ethyl-4-[2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate(3.3 g, 8.39 mmol) in TFA (3 mL)/DCM (6 mL) was stirred at 30° C. for 2hrs. The resulting mixture was concentrated under vacuum. This resultedin 3.3 g (97%) of the title compound as a brown oil. LCMS (M+H)⁺: 294.1.

Step 1-3, preparation of tert-butyl(3R)-4-[4-bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate:2-chloro-4-(trifluoromethyl)benzoic acid (860 mg, 3.83 mmol, 1.2 eq.)and HATU (1.46 g, 3.83 mmol, 1.2 eq.) were dissolved in DMF (20 mL).After stirring for 5 min at rt, the resulting solution was treated withmethyl 2-[(2R)-2-ethylpiperazin-1-yl]-5-nitrobenzoate trifluoroacetate(1.3 g, 3.19 mmol) and DIEA (1.23 g, 9.57 mmol, 3.0 eq.). The reactionwas stirred for 1 h at room temperature, diluted with water (50 mL), andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (2×50 mL), dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified by a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:1). 1.8 g (83%) ofthe title compound was obtained as a yellow oil. LCMS (M+H)⁺: 500.1.

Step 1-4, preparation of5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate:into a 40-mL round-bottom flask, was placed methyl2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-nitrobenzoate(1.8 g, 3.60 mmol), Fe (1 g, 18.00 mmol, 5.0 eq.), NH₄Cl (963 mg, 18.00mmol, 5.0 eq.), and EtOH (20 mL)/H₂O (4 mL). The resulting solution wasstirred at 70° C. for 1 h and cooled to rt. The reaction was dilutedwith water (50 mL) and extracted with ethyl acetate (3×60 mL). Thecombined organic layers were dried and concentrated under vacuum. Theresidue was purified by a silica gel column eluting with ethylacetate/petroleum ether (1:1). 1.1 g (65%) of the title compound wasisolated as a yellow oil. LCMS (M+H)⁺: 470.1.

Step 1-5, preparation of methyl5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate:into a 40-mL round-bottom flask, was placed CuBr₂ (1.31 g, 5.85 mmol,2.5 eq.), n-butyl nitrite (482 mg, 4.68 mmol, 2.0 eq.), and ACN (20 mL).The resulting solution was stirred for 5 min at 0° C. and treated with asolution of methyl5-amino-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate(1.1 g, 2.34 mmol) in ACN (5 mL) dropwise at 0° C. The resultingsolution was stirred at 50° C. for 1 h. The reaction mixture was cooledto rt and diluted with water (50 mL). The resulting solution wasextracted with ethyl acetate (3×50 mL). The combined organic layers weredried and concentrated under vacuum. The residue was purified by asilica gel column eluting with ethyl acetate/petroleum ether (1:1). 520mg (42%) of the title compound was isolated as a light yellow oil. LCMS(M+H)⁺: 533.0.

Step 1-6, preparation of methyl4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxylate:Into a 8-mL pressure tube vessel, was placed methyl5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoate(30 mg, 0.06 mmol), 2,3-difluorophenylboronic acid (13.3 mg, 0.08 mmol),Pd₂(dba)₃CHCl₃ (5.8 mg, 0.01 mmol), P(t-Bu)₃.HBF₄ (1.6 mg, 0.01 mmol),K₃PO₄ (35.8 mg, 0.17 mmol), and toluene/H₂O (1 mL/0.1 mL). The resultingsolution was degassed for 5 min with N₂, sealed, and stirred at 70° C.for 2 hrs in an oil bath. The resulting mixture was cooled to rt andconcentrated under vacuum. The residue was applied onto a silica gelcolumn eluting with ethyl acetate/petroleum ether (1:3), resulting in 20mg (63%) of the title compound. LCMS (M+H)⁺: 567.1.

Step 1-7, preparation ofN-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide:a 8-mL pressure tube vessel, was placed methyl methyl4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxylate(20 mg, 0.04 mmol), ethane-1,2-diamine (0.5 mL), and IPA (0.5 mL). Theresulting solution was sealed and stirred at 70° C. for 16 hrs. Theresulting mixture was cooled to rt and concentrated under vacuum. Theresidue was purified by Prep-HPLC with the following conditions: SunFirePrep C18 OBD column; mobile phase, phase A: water (0.05% TFA); phase B:ACN (30% up to 45% in 6 min); flow rate: 20 mL/min; detector, 220 & 254nm, resulting in 7.4 mg (30%) of the title compound. LCMS (M+H)⁺: 595.2.

The following compounds were prepared similarly to Example 1 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings.

Compound MS no. (M + H)⁺ 1-2 589.1 1-3 603.1 1-4 577.2 1-5 593.2 1-6593.2 1-7 584.2 1-8 573.2 1-9 611.1 1-10 603.2 1-11 617.2 1-12 617.31-13 575.2 1-16 603.2 1-22 588.2 1-23 617.3 1-28 601.2 1-29 601.2 1-30560.2 1-31 560.2 1-34 604.3

Example 2:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxamide(Compound 1-14)

Step 2-1, preparation of methyl2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate:Into a 8-mL pressure tube vessel purged and maintained with an inertatmosphere of nitrogen, was placed methyl5-bromo-2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]benzoatefrom Example 1, Step 1-5 (250 mg, 0.47 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(178 mg, 0.70 mmol), Pd(DTBPF)Cl₂ (25 mg, 0.04 mmol), KOAc (138 mg, 1.4mmol), and dioxane (5 mL). The resulting solution was degassed for 10min with N₂, sealed, and stirred at 90° C. for 3 h in an oil bath. Theresulting mixture was cooled to rt and concentrated under vacuum. Theresidue was applied onto a silica gel column eluting with ethylacetate/petroleum ether (1:3). This resulted in 120 mg (44%) of thetitle compound. LCMS (M+H)⁺: 581.2.

Step 2-2, preparation of methyl4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxylate:to a 8-mL pressure tube vessel, was placed2-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(43 mg, 0.07 mmol), 1-bromo-2-cyclopropoxybenzene (28 mg, 0.13 mmol),Pd(DTBPF)Cl₂ (2 mg, 0.003 mmol), K₂CO₃ (20 mg, 0.14 mmol), anddioxane/H₂O (2 mL/0.2 mL). The resulting solution was degassed for 10min with N₂, sealed, and stirred at 90° C. for 2 h in an oil bath. Thereaction mixture was cooled to rt and concentrated under vacuum. Theresidue was purified by a prep-TLC with ethyl acetate/petroleum ether(1:3), resulting in 25 mg (57%) of the title compound. LCMS (M+H)⁺:587.0.

Step 2-3, preparation ofN-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxamide:to a 8-mL pressure tube vessel, was placed methyl4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxylate(25 mg, 0.04 mmol), ethane-1,2-diamine (2 mL), and IPA (2 mL). Theresulting solution was sealed and stirred at 70° C. for 16 h. Theresulting mixture was cooled to rt and concentrated under vacuum. Theresidue was purified by Prep-HPLC with the following conditions: SunFirePrep C18 OBD column; mobile phase, phase A: water (0.05% TFA); phase B:ACN (21% up to 38% in 6 min); flow rate: 20 mL/min; detector, 220 & 254nm, yielding 10.7 mg (34%) of the title compound. LCMS (M+H)⁺: 615.2.

The following compounds were prepared similarly to Example 2 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 1-32 604.2 1-33 604.2 1-35 604.2

Example 3:6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide(Compound 1-95)

Step 3-1, preparation of tert-butyl(3R)-3-ethyl-4-[3-fluoro-2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate:to a solution of tert-butyl-(3R)-3-ethylpiperazine-1-carboxylate (555mg, 2.59 mmol) and methyl 2,6-difluoro-3-nitrobenzoate (843 mg, 3.89mmol) in DMSO (2 mL) was added DIEA (0.90 mL, 5.2 mmol). The mixture washeated at 130° C. for 1 h. The mixture was purified by C18 reversedphase column chromatography to give the title compound (813 mg, 76%yield) as a brownish yellow gum. LCMS (M+H)⁺: 412.3.

Step 3-2, preparation of tert-butyl(3R)-4-[4-amino-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate:to a solution of tert-butyl(3R)-3-ethyl-4-[3-fluoro-2-(methoxycarbonyl)-4-nitrophenyl]piperazine-1-carboxylate(813 mg, 1.98 mmol) in MeOH (30 mL) was added 10% Pd/C (213 mg, 0.0941mmol) and NH₄Cl (1.188 g, 18.83 mmol). The mixture was heated at 80° C.for 20 min. The mixture was filtered through Celite and the filtrate wasconcentrated and purified by C18 reversed phase column chromatography togive the title compound (612 mg, 81% yield) as a reddish brown gum. LCMS(M+H)⁺: 382.3.

Step 3-3, preparation of tert-butyl(3R)-4-[4-bromo-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate:to a solution of tert-butyl(3R)-4-[4-amino-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate(612 mg, 1.60 mmol) in MeCN (10 mL) under nitrogen was added CuBr₂ (197mg, 0.882 mmol) and 90% tert-butyl nitrite (0.24 mL, 1.8 mmol). Themixture was heated at 70° C. for 30 min. The mixture was quenched withice water and extracted with DCM (3×). The combined organic layers werewashed with saturated NaHCO₃ (aq), concentrated, and purified by C18reversed phase column chromatography to give the title compound (267 mg,0.600 mmol, 38% yield) as a brown gum. LCMS (M+H)⁺: 445.2.

Step 3-4, preparation of tert-butyl(3R)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate:to a mixture of tert-butyl(3R)-4-[4-bromo-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate(267 mg, 0.600 mmol), (2-ethoxypyridin-3-yl)boronic acid (150 mg, 0.900mmol), Pd[t-Bu₂P(4-NMe₂C₆H₄)]₂Cl₂) (42.5 mg, 0.0600 mmol), and K₂CO₃(249 mg, 1.80 mmol) in a sealed tube was added dioxane (4 mL) and H₂O(0.4 mL). The resulting solution was degassed with N₂ (g) for 10 min,sealed, and stirred at 100° C. for 30 min. The reaction was treated withadditional (2-ethoxypyridin-3-yl)boronic acid (37.8 mg, 0.226 mmol),Pd[t-Bu₂P(4-NMe₂C₆H₄)]₂Cl₂) (13.4 mg, 0.0189 mmol), and K₂CO₃ (78.3 mg,0.567 mmol) and stirred at 100° C. for additional 30 min. The mixturewas concentrated and purified by C18 reversed phase columnchromatography to give the title compound (255 mg, 87% yield) as a browngum. LCMS (M+H)⁺: 488.4.

Step 3-5, preparation of6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid: to a solution of tert-butyl(3R)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylate(255 mg, 0.523 mmol) in THF/MeOH/H₂O (4.5/1.5/1.5 mL) was added LiOH.H₂O(220 mg, 5.24 mmol). The mixture was heated at 60° C. overnight. About50% of the reaction was completed. After addition of additional LiOH.H₂O(220 mg, 5.24 mmol), the mixture was continued to heat at 70° C. for 2days. After removal of volatile solvent, the aqueous residue was dilutedwith ice water and acidified with 1N HCl (aq) to pH 4. The solid wascollected by vacuum filtration and dried to give the title compound (239mg, 97% yield) as a brown solid. LCMS (M+H)⁺: 474.2.

Step 3-6, preparation of3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoicacid dihydrochloride: to a solution of6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid (100 mg, 0.211 mmol) in DCM (0.3 mL) was added 4N HCl in dioxane(0.30 mL, 1.2 mmol). The mixture was stirred at rt for 1 hr. Thesolution was decanted and the residue was rinsed with DCM (3×) and driedunder vacuum to give the title compound as a medium brown solid. LCMS(M+H)⁺: 374.3.

Step 3-7, preparation of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid: to a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (94.9mg, 0.423 mmol) and HATU (145 mg, 0.381 mmol) in DMF (0.5 mL) was addedDIEA (0.073 mL, 0.42 mmol). After stirring at rt for 5 min, theresulting solution was added to a solution of3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzoicacid dihydrochloride (0.211 mmol) and DIEA (0.11 mL, 0.42 mmol) in DMF(0.2 mL). The mixture was stirred at RT for 10 min. The reaction wasdirectly purified by C18 reversed phase column chromatography to givethe title compound (69.8 mg, 57% yield) as a white solid. LCMS (M+H)⁺:580.3.

Step 3-8, preparation of tert-butylN-[2-({6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}formamido)ethyl]-N-methylcarbamate:to a solution of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid (35.0 mg, 0.06 mmol) and HATU (34.4 mg, 0.091 mmol) in DMF (0.2 mL)was added DIEA (0.021 mL, 0.12 mmol). After stirring at rt for 5 min,the reaction was treated with tert-butylN-(2-aminoethyl)-N-methylcarbamate (21.0 mg, 0.121 mmol) and stirred atrt for 5 min. The mixture was purified by C18 reversed phase columnchromatography to give the title compound (35.6 mg, 80% yield) as anoff-white solid. LCMS (M+H)⁺: 736.4.

Step 3-9, preparation of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylaminoethyl]benzamide:To a solution of tert-butylN-[2-({6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl}formamido)ethyl]-N-methylcarbamate(35.6 mg, 0.0484 mmol) in DCM (0.1 mL) was added 4N HCl in dioxane (0.10mL, 0.40 mmol). The mixture was stirred at rt for 10 min. The solutionwas decanted and the residue was rinsed with DCM (3×) and dried undervacuum. The HCl salt of product was triturated with saturated NaHCO₃(aq) and dried to give the title compound (24.6 mg, 80% yield) as anoff-white solid. LCMS (M+H)⁺: 636.3.

The following compounds were prepared similarly to Example 3 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings. In some examples,the final deprotecting step may not be required:

Compound MS no. (M + H)⁺ 1-15 569.2 1-19 617.2 1-20 616.2 1-21 630.21-25 603.3 1-45 630.4 1-46 618.3 1-48 644.5 1-49 658.5 1-69 622.3 1-92630.5 1-97 630.5 1-98 644.5 1-99 644.5 1-100 644.4 1-102 630.6 1-108644.4 1-109 660.2 1-112 648.3 1-123 648.4 1-124 662.3 1-138 660.3 1-198634.3 1-199 662.3 1-200 648.4 1-201 662.3 1-202 630.4 1-203 644.5 1-204648.5 3-5 604.2 3-6 590.3 1-216 630.5 1-217 659.2

Example 4:6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide(Compound 1-173)

Step 4-1, preparation of tert-butyl(3R)-4-(2-{[2-(dimethylamino)ethyl]carbamoyl}-4-(2-ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1-carboxylate:to a solution of6-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid from Example 3, step 3-5 (1.000 g, 2.111 mmol) and HATU (963 mg,2.53 mmol) in DMF (1 mL) was added DIEA (0.92 mL, 5.3 mmol). Afterstirring at RT for 5 min, the resulting solution was treated with(2-aminoethyl)dimethylamine (0.35 mL, 3.1 mmol) and stirred at rt for 10min. The reaction was purified by C18 reversed phase columnchromatography to give the title compound (973.7 mg, 85% yield) as alight yellow solid. LCMS (M+H)⁺: 544.4.

Step 4-2, preparation ofN-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzamidetrihydrochloride: to a solution of tert-butyl(3R)-4-(2-{[2-(dimethylamino)ethyl]carbamoyl}-4-(2-ethoxypyridin-3-yl)-3-fluorophenyl)-3-ethylpiperazine-1-carboxylate(973.7 mg, 1.791 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2.3mL, 9.2 mmol). The mixture was stirred at rt for 2 hrs. The reaction wastreated with additional 4N HCl in dioxane (2.0 mL, 8.0 mmol) andcontinued to stir for 2 hrs. The solution was decanted and the residuewas rinsed with DCM (3×) and dried under vacuum to give the titlecompound as a light yellow solid. LCMS (M+H)⁺: 444.3.

Step 4-3, preparation of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide:to a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (40.6 mg,0.181 mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0.2 mL) was addedDIEA (0.047 mL, 0.27 mmol). After stirring at rt for 5 min, theresulting solution was added to a solution ofN-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzamidetrihydrochloride (40.0 mg, 0.0723 mmol) and DIEA (0.110 mL, 0.631 mmol)in DMF (0.2 mL). After stirring at rt for 10 min, the reaction waspurified by C18 reversed phase column chromatography to give the titlecompound (35.3 mg, 75% yield) as an off-white solid. LCMS (M+H)⁺: 650.3.

The following compounds were prepared similarly to Example 4 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings. In some examples, anadditional deprotection is required in the final step:

Compound MS no. (M + H)⁺ 1-37 604.4 1-38 554.2 1-39 597.3 1-42 570.21-43 550.2 1-47 632.4 1-53 571.2 1-54 566.3 1-55 561.2 1-58 588.3 1-59584.0 1-60 530.3 1-61 605.3 1-62 570.4 1-63 542.4 1-71 590.3 1-72 648.31-73 598.2 1-74 603.4 1-76 614.4 1-77 531.5 1-78 534.3 1-79 550.3 1-80546.3 1-81 558.4 1-82 580.3 1-86 531.4 1-87 550.3 1-88 556.4 1-89 555.51-91 605.4 1-96 586.2 1-105 656.4 1-106 614.4 1-107 613.4 1-110 594.31-111 632.3 1-113 582.2 1-114 620.4 1-117 561.3 1-118 589.4 1-119 600.21-120 640.4 1-121 602.5 1-122 614.4 1-126 586.3 1-127 614.3 1-129 614.31-130 613.3 1-131 614.3 1-133 597.4 1-134 631.5 1-142 587.3 1-143 626.51-144 621.5 1-145 586.3 1-146 614.3 1-147 591.4 1-153 593.2 1-154 627.21-155 632.4 1-156 602.4 1-157 627.4 1-159 601.3 1-160 560.4 1-161 603.31-162 617.4 1-163 632.3 1-164 633.3 1-165 647.3 1-166 633.3 1-168 646.41-174 634.4 1-175 641.4 1-179 616.3 1-186 607.1 1-191 605.3 1-192 585.21-193 571.2 1-228 644.5 1-229 662.2 1-270 659.4 1-271 645.5

Example 5:6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide(Compound 1-184)

Step 5-1, preparation of 4-chloro-2-(difluoromethyl)benzoic acid: to amixture of 4-chloro-2-methylbenzoic acid (0.460 g, 2.70 mmol),Selectfluor (2.697 g, 7.612 mmol) and Na₂S₂O₈ (0.365 g, 1.53 mmol) in asealed tube was added MeCN (2 mL) and water (2 mL). N₂ (g) was bubbledand then the mixture was cooled to −78° C. under nitrogen and AgNO₃(51.8 mg, 0.305 mmmol) was added. After addition, the mixture was warmedto rt under nitrogen and then heated at 80° C. for 3 hrs, filteredthrough Celite and rinsed with EtOAc. The filtrate was washed withsaturated NaHCO₃ (aq) (3×25 mL). The combined basic aqueous solution wasacidified with 1N HCl (aq) to pH 2-3 and extracted with EtOAc (2×). Thecombined organic layers were concentrated and purified by C18 reversedphase column chromatography to give the title compound (128.8 mg, 23%yield) as an off-white solid.

Step 5-2, preparation of6-[(2R)-4-[4-chloro-2-(difluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide:to a solution of 4-chloro-2-(difluoromethyl)benzoic acid (37.3 mg, 0.181mmol) and HATU (61.9 mg, 0.163 mmol) in DMF (0.2 mL) was added DIEA(0.047 mL, 0.27 mmol). After stirring at rt for 5 min, the resultingsolution was added to a solution ofN-[2-(dimethylamino)ethyl]-3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorobenzamidetrihydrochloride from Example 4, step 4-2 (43.0 mg, 0.0778 mmol) andDIEA (0.110 mL, 0.631 mmol) in DMF (0.2 mL). The mixture was stirred atrt for 10 min. The mixture was purified by C18 reversed phase columnchromatography to give the title compound (20.6 mg, 0.0326 mmol, 41.9%yield) as an off-white solid. LCMS (M+H)⁺: 632.3.

The following compounds were prepared similarly to Example 5 withappropriate substituting reagents and substrates at different steps. Insome examples, an additional deprotection is required in the final step:

Compound MS no. (M + H)⁺ 1-128 600.4 1-176 616.5 1-177 602.5 1-183 618.61-189 614.4 1-190 630.6 1-210 615.4 1-213 601.4

Example 6:6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide(Compound 1-188)

Step 6-1, preparation of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzamide:to a solution of6-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorobenzoicacid from Example 3, step 3-7 (48 mg, 0.082 mmol) in ACN (1 mL) wasadded HATU (31 mg, 0.082 mmol) and Et₃N (17 μL, 0.12 mmol). Afterstirring for 5 min at rt, the resulting solution was treated with(4,5-dihydro-1H-imidazol-2-yl)methylamine dihydrochloride (14 mg, 0.081mmol) which was pre-neutralized with Et₃N (34 μL, 0.24 mmol) in ACN (1mL). The reaction was stirred at rt for 20 min, diluted with DCM, andwashed with H₂O and brine. The organic layer was dried with anhydrousNa₂SO₄ and concentrated. The residue was purified from a silica gelcolumn chromatography eluting with DCM/MeOH (100/0 to 85/15) to affordthe title compound (21 mg, 39%). LCMS (M+H)⁺: 661.2.

The following compounds were prepared similarly to Example 6 withappropriate substituting reagents and substrates at different steps:

Compound MS no. (M + H)⁺ 1-64 652.4 1-65 652.4 1-66 652.4 1-70 638.21-83 641.4 1-84 655.6 1-93 655.1 1-116 673.4 1-125 643.4 1-132 641.31-139 656.6 1-140 630.6 1-141 649.5 1-170 657.5 1-178 627.3 1-182 645.41-219 675.2 1-224 640.3 1-226 644.5 1-227 658.4 1-234 670.4

Example 7:N-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide(Compound 1-57)

Step 7-1, preparation of2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoicacid: to a 15-mL pressure tube vessel, was placed a solution of4-chloro-2-fluorobenzoic acid methyl ester (80 mg, 0.42 mmol),pyrrolidin-3-yl-carbamic acid tert-butyl ester (118 mg, 0.63 mmol), andDIEA (0.11 mL, 0.63 mmol) in DMSO (2 mL). The resulting solution wasstirred at 140° C. for 2.5 hrs in an oil bath. The reaction progress wasmonitored by LCMS. The resulting mixture was cooled to rt and purifiedfrom C18 reversed phase column chromatography with 0.1% TFA-ACN/0.1%TFA-H₂O to afford2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoicacid methyl ester (150 mg, 100%). LCMS (M+H)⁺: 355.3. To a 25-mLround-bottom flask, was placed a solution of2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoicacid methyl ester (150 mg, 0.42 mmol) in H₂O/MeOH/THF (0.6/0.6/1.8 mL).The resulting solution was treated with LiOH monohydrate (170 mg, 4.2mmol) and stirred overnight at 70° C. The reaction was cooled to rt,concentrated, and then diluted with H₂O (˜2 mL). The resulting solutionwas acidified with 1N—HCl, and then extracted with EtOAc (2×). Thecombined organic layers were washed with brine, dried, and concentratedto afford2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoicacid (110 mg, 82%). LCMS (M+H)⁺: 341.1.

Step 7-2, preparation of benzylN-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate:to a 10-mL round-bottom flask, was placed a solution of2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoicacid (25 mg, 0.073 mmol) in ACN (1.0 mL). The solution was treated withHATU (30 mg, 0.079 mmol) and Et₃N (11 μL, 0.079 mmol). After stirringfor 5 min, the resulting solution was treated with benzylN-(2-{[5-(2-ethoxypyridin-3-yl)-2-[(2R)-2-ethylpiperazin-1-yl]phenyl]formamido}ethyl)carbamate (40 mg, 0.073 mmol) and stirred at rt for 20 min. Theresulting mixture was directly purified from C18 reversed phase columnchromatography with 0.1% TFA-ACN/0.1% TFA-H₂O to afford benzylN-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate(30 mg, 48%). LCMS (M+H)⁺: 854.5.

Step 7-3, preparation ofN-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-ylbenzamide:A solution of benzylN-[2-({2-[(2R)-4-{2-[(3S)-3-{[(tert-butoxy)carbonyl]amino}pyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)phenyl}formamido)ethyl]carbamate(28 mg, 0.032 mmol) and catalytic amount of thioanisole (1˜2 drops) inTFA (0.5 mL) was stirred at 60° C. for 30 min. The reaction was cooledto rt and concentrated. The residue was purified from C18 reversed phasecolumn chromatography with 0.1% TFA-ACN/0.1% TFA-H₂O to affordN-(2-aminoethyl)-2-[(2R)-4-{2-[(3S)-3-aminopyrrolidin-1-yl]-4-chlorobenzoyl}-2-ethylpiperazin-1-yl]-5-(2-ethoxypyridin-3-yl)benzamide(13 mg, 65%). LCMS (M+H)⁺: 620.5.

The following compounds were prepared similarly to Example 7 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings. In some examples,the acid-catalyzed deprotection is not required in the final step:

Compound MS no. (M + H)⁺ 1-40 634.3 1-41 634.2 1-50 668.3 1-51 618.31-52 634.3 1-56 618.4 1-67 614.4 1-68 628.6 1-90 646.5 1-94 640.3 1-101644.6 1-103 644.7 1-104 614.4 1-115 674.4 1-148 618.6 1-180 694.5 1-197680.4

Example 8:N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide(Compound 1-17)

Step 8-1, preparation of benzylN-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate:to a 10-mL round-bottom flask, was placed a solution of2-bromo-4-fluorobenzoic acid (40 mg, 0.18 mmol) in ACN (2.0 mL). Thesolution was treated with HATU (76 mg, 0.2 mmol) and Et₃N (36 μL, 0.27mmol). After stirring for 5 min, the resulting solution was treated withbenzylN-[2-({2′-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamatetrifluoroacetate (120 mg, 0.18 mmol) and stirred at rt for 20 min. Theresulting mixture was directly purified from C18 reversed phase columnchromatography eluting with 0.1% TFA-ACN/0.1% TFA-H₂O to afford benzylN-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate(54 mg, 41%). LCMS (M+H)⁺: 731.5.

Step 8-2, preparation of benzylN-[2-({4-[(2R)-4-[4′-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate:to a 15-mL pressure tube vessel, was placed benzylN-[2-({4-[(2R)-4-(2-bromo-4-fluorobenzoyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate(50 mg, 0.068 mmol), [4-({[(tert-butoxy)carbonyl]amino}methyl)phenyl]boronic acid (35 mg, 0.14 mmol), PdCl₂(t-Bu₂PPhNMe₂)₂ (5 mg,0.007 mmol), K₂CO₃ (19 mg, 0.14 mmol), and dioxane/H₂O (2 mL/0.2 mL).The resulting solution was degassed with N₂ for 5 min and then sealedwith a cap. The reaction was stirred at 85° C. for 2 hrs in an oil bath.The resulting mixture was cooled to rt, diluted with EtOAc, and washedwith 1N—HCl and brine. The organic layer was dried with anhydrous MgSO₄and concentrated. The residue was purified from C18 reversed phasecolumn chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H₂O to affordbenzyl N-[2-({4-[(2R)-4-[4′-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate(43 mg, 74%). LCMS (M+H)⁺: 858.8.

Step 8-3, preparation ofN-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide:a solution of benzylN-[2-({4-[(2R)-4-[4′-({[(tert-butoxy)carbonyl]amino}methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}formamido)ethyl]carbamate(43 mg, 0.050 mmol) and catalytic amount of thioanisole (1˜2 drops) inTFA (0.5 mL) was stirred at 60° C. for 30 min. The reaction was cooledto rt and concentrated. The residue was purified from C18 reversed phasecolumn chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H₂O to affordN-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide(22 mg, 71%). LCMS (M+H)⁺: 624.4.

The following compounds were prepared similarly to Example 8 withappropriate substituting reagents and substrates at different steps.Some examples may require —CN reduction to introduce the benzyl amine inthe final step:

Compound MS no. (M + H)⁺ 1-18 620.5 1-24 606.3 1-26 624.4 1-27 638.51-36 625.6 1-44 639.4 1-75 612.3 1-85 612.4

Example 9.5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-135)

Step 9-1, preparation of2′-ethoxy-5-fluoro-[2,3′-bipyridine]-6-carbonitrile: to a solution ofthe mixture of 6-bromo-3-fluoropyridine-2-carbonitrile and6-chloro-3-fluoropyridine-2-carbonitrile (4:1 ratio, 1.0 equiv, 1.0mmol, 200 mg) in dioxane (4 mL) was added Pd(Amphos)Cl₂ (0.025 equiv,0.025 mmol, 18 mg), 2-ethoxypyridin-3-ylboronic acid (2.0 equiv, 2.0mmol, 334 mg), K₂CO₃ (2.2 equiv, 2.2 mmol, 304 mg) and water (0.4 mL).The resulting solution was purged with nitrogen and heated at 100° C.for 1 h. LCMS showed complete consumption of starting material andformation of desired product. This reaction was repeated on 5.0 mmolscale under similar conditions. These two batches of reaction mixturewere combined, diluted with ethyl acetate (50 mL), washed with water andbrined, dried with anhydrous Na₂SO₄, filtered and concentrated. Theremaining residue was purified by silica gel chromatography eluting withEtOAc/hexane (0-50%) to afford 1.7 g (>100%) of the desired productcontaining unidentified impurities. LCMS (M+H)⁺=244.1.

Step 9-2, preparation of tert-butyl(3R)-4-{6-cyano-2′-ethoxy-[2,3′-bipyridin]-5-yl}-3-ethylpiperazine-1-carboxylate:to a solution of 2′-ethoxy-5-fluoro-[2,3′-bipyridine]-6-carbonitrile(1.0 equiv, 6.0 mmol, 1.7 g) in DMSO (10 mL) was added tert-butyl(3R)-3-ethylpiperazine-1-carboxylate (1.5 equiv, 9.0 mmol, 1.9 g) andDIEA (2.0 equiv, 12 mmol, 2.0 mL). The resulting solution was purgedwith nitrogen and heated at 140° C. for 2 days. LCMS showed the desiredproduct formed but Boc protecting group was partially lost. Thus, thereaction was cooled to rt and followed by addition of DIPEA (2.0 equiv,12 mmol, 2.0 mL) and di-tert-butyl dicarbonate (2.0 equiv, 12 mmol, 2.75mmol) and stirred for 1 h. Then reaction solution was diluted with ethylacetate (50 mL), washed with water and brine, dried with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by C18reversed phase column chromatography eluting with MeCN/water (5-100%).Pure fractions were combined, neutralized with saturated NaHCO₃, andextracted with ethyl acetate. The combined organic layers were driedwith MgSO₄, concentrated, and dried under high vacuum to give 1.20 g(46%) of the desired product. LCMS (M+H)⁺=438.3.

Step 9-3, preparation of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitriletrifluoroacetate: to a solution of tert-butyl(3R)-4-{6-cyano-2′-ethoxy-[2,3′-bipyridin]-5-yl}-3-ethylpiperazine-1-carboxylate(1.0 equiv, 0.73 mmol, 320 mg) in DCM (3.0 mL) was added TFA (1.0 mL).The resulting mixture was stirred at ambient temperature for 1 h. Thereaction was concentrated under vacuum to afford crude product (560 mg)as TFA salt. This material was used for next step without furtherpurification. LCMS (M+H)⁺=338.4.

Step 9-4, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile:to a solution of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitriletrifluoroacetate (560 mg crude, 0.73 mmol,) in DMF (3.0 mL) was addedDIEA (1.06 mL, 4.38 mmol, 6.0 eq.), HATU (570 mg, 1.5 mmol, 2.0 eq.) and2-trifluoromethyl-4-chlorobenzoic acid (224 mg, 1.0 mmol, 1.35 eq.). Theresulting mixture was stirred at rt for 10 min and LCMS showed completeconsumption of starting material. The reaction solution was diluted withethyl acetate (50 mL), washed with water and brine, with anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography eluting with EtOAc/hexane (0-50%) to afford 230 mg(58%) of the desired product. LCMS (M+H)⁺=544.3.

Step 9-5, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid: to a solution of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile(27 mg, 0.05 mmol,) in EtOH (0.25 mL) was added KOH (85%, 28 mg, 0.50mmol, 10 eq.) and water (0.25 mL). The resulting mixture was heated at100° C. for overnight. The reaction mixture was cooled to rt, dilutedwith ethyl acetate (10 mL), washed with saturated NaHSO₄ (5.0 mL) andbrine, dried and concentrated to afford 26 mg of crude title compound.This material was used for next step without further purification. LCMS(M+H)⁺=563.3.

Step 9-6, preparation of tert-butylN-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}formamido)ethyl]-N-methylcarbamate:to a solution of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid (26 mg, 0.05 mmol) in DMF (0.5 mL) was added DIEA (0.10 mL, 0.55mmol, 11 eq.), HATU (38 mg, 0.10 mmol, 2.0 eq.) and1-boc-1-methylethylenediamine (19 mg, 0.10 mmol, 2.0 eq.). The resultingmixture was stirred at ambient temperature for 0.5 h. The crude reactionsolution was purified by a C18 reversed phase column chromatographyeluting with MeCN/water (5-100%). Pure fractions were combined,neutralized with saturated NaHCO₃ and NaCl, extracted with ethyl acetateand dried with MgSO₄. The organic layer was concentrated and dried underhigh vacuum to give 15 mg (47%) of the desired product. LCMS(M+H)⁺=719.3.

Step 9-7, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[2-(methylamino)ethyl]-[2,3′-bipyridine]-6-carboxamide:to a solution of tert-butylN-[2-({5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}formamido)ethyl]-N-methylcarbamate(15 mg, 0.021 mmol) in DCM (0.5 mL) was added TFA (0.2 mL). Theresulting mixture was stirred at ambient temperature for 0.5 h. Thereaction was concentrated and purified by a C18 reversed phase columnchromatography eluting with MeCN/water (5-60%). Pure fractions werecombined, neutralized with saturated NaHCO₃ and NaCl, extracted withethyl acetate and dried with MgSO₄. The organic layer was concentratedand dried under high vacuum to give 9 mg (70%) of the desired product.LCMS (M+H)⁺=619.4.

The following compounds were prepared similarly to Example 9 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings. In some examples, anadditional deprotection is not required in the final step.

Compound MS no. (M + H)⁺ 1-136 602.6 1-137 629.6 1-149 632.3 1-151 631.41-167 615.4 1-171 576.4 1-172 594.5 1-181 630.6 1-185 600.4 1-187 616.61-194 603.4 1-195 595.3 1-205 617.4 1-206 644.4 1-208 618.6 1-209 630.51-211 617.5 1-214 631.4 1-215 645.5 1-218 607.3 1-220 616.3 1-221 630.51-222 631.3 1-223 645.4 1-230 628.4 1-231 645.3 1-232 645.5 1-233 642.41-236 627.4 1-237 641.4 1-239 642.5 1-240 628.5 1-242 642.5 1-243 656.51-244 628.4 1-245 642.4 1-246 614.3 1-247 628.4 1-249 656.6 1-256 642.41-257 656.6 1-268 646.3 1-269 632.3 1-272 632.1 1-275 649.3 1-276 649.51-289 646.4 1-290 660.5 1-291 646.5 1-296 660.3 1-303 581.2

Example 10.5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamideAcetate (Compound 1-150)

Step 10-1, preparation of5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid: to a solution of tert-butyl(3R)-4-{6-cyano-2′-ethoxy-[2,3′-bipyridin]-5-yl}-3-ethylpiperazine-1-carboxylatefrom Example 9, step 9-2 (271 mg, 0.62 mmol) in EtOH (3 mL) was addedKOH (85%, 409 mg, 6.2 mmol, 10 eq.) and water (3.0 mL). The resultingmixture was heated at 100° C. for overnight. The reaction mixture wascooled to rt, diluted with ethyl acetate (10 mL), washed with saturatedNaHSO₄ (10 mL) and brine, dried and concentrated to afford 283 mg ofcrude title compound. This material was used for next step withoutfurther purification. LCMS (M+H)⁺=457.3.

Step 10-2, preparation of tert-butyl(3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate:to a solution of5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid (283 mg, 0.619 mmol) in DMF (5.0 mL) was added HATU (353 mg, 0.93mmol, 1.5 eq.), DIEA (0.31 mL, 1.86 mmol, 3.0 eq.) andN,N-dimethylethylenediamine (84 mg, 0.93 mmol, 1.5 eq.). The resultingmixture was stirred at 50° C. for 0.5 h. The reaction mixture wasdiluted with ethyl acetate, washed with water and brine, dried withNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography eluting with MeOH/DCM (0-15%) to afford 396 mg of thedesired product as brown oil. LCMS (M+H)⁺=527.4.

Step 10-3, preparation ofN-[2-(dimethylamino)ethyl]-2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of tert-butyl(3R)-4-(6-{[2-(dimethylamino)ethyl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(396 mg, 0.75 mmol) in DCM (4.0 mL) was added TFA (2.0 mL). Theresulting mixture was stirred at ambient temperature for 0.5 h andconcentrated under vacuum. The residue was neutralized with saturatedNaHCO₃, extracted with ethyl acetate, dried with Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatographyeluting with MeOH/DCM (0-20%) to afford 201 mg (64%) of the desiredproduct as brown oil. LCMS (M+H)⁺=427.4.

Step 10-4, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-N-[2-(dimethylamino)ethyl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxamideacetate: to a solution ofN-[2-(dimethylamino)ethyl]-2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carboxamide(89 mg, 0.20 mmol) in DMF (2 mL) was added HATU (91 mg, 0.24 mmol, 1.2eq.), DIEA (0.092 mL, 0.50 mmol, 2.5 eq) and2-trifluoromethyl-4-chlorobenzoic acid (45 mg, 0.20 mmol, 1.0 eq.). Theresulting mixture was heated at 50° C. for 0.5 h. The reaction mixturewas diluted with ethyl acetate, washed with water and brine, dried withNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography eluting with MeOH/DCM (0-9%). Pure fraction werecombined and concentrated with HOAc (0.1 mL) to afford 90 mg (64%) ofthe desired product. LCMS (M+H)⁺=633.4.

The following compounds were prepared similarly to Example 10 withappropriate substituting reagents and substrates at different steps. Insome examples, an additional deprotection is required in the final step.

Compound MS no. (M + H)⁺ 1-158 590.1 1-169 629.5 1-196 609.3 1-207 644.51-225 629.3 1-253 641.1 1-254 627.4 1-258 629.4 1-259 611.2 1-260 602.41-266 615.2 1-267 597.2 1-277 588.2

Example 11:3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide(Compound 3-8)

Step 11-1, preparation of methyl6-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylate:to a 15-mL pressure tube vessel, was placed6-bromo-3-chloropyrazine-2-carboxylic acid methyl ester (300 mg, 1.19mmol), tert-butyl (3R)-3-ethylpiperazine-1-carboxylate (370 mg, 1.72mmol, 1.4 equiv), DIEA (0.3 mL, 1.78 mmol, 1.5 equiv), and DMSO (6 mL).The resulting solution was stirred at 140° C. for 1 h, cooled to rt, anddiluted with EtOAc (˜15 mL). The organic layer was washed with 1N HCl(2×) and brine (1×), dried with anhydrous Na₂SO₄, and concentrated. Theresidue was purified from C18 reversed phase column chromatographyeluting with 0.1% TFA-ACN/0.1% TFA-H₂O. 140 mg (27%) of methyl6-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylatewas isolated. LCMS (M+H)⁺: 429.3.

Step 11-2, preparation of methyl3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate:to a 15-mL pressure tube vessel, was placed66-bromo-3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]pyrazine-2-carboxylate(100 mg, 0.23 mmol), 2-ethoxypyridine-3-boronic acid (78 mg, 0.46 mmol),PdCl₂(t-Bu₂PPhNMe₂)₂ (24 mg, 0.033 mmol), K₂CO₃ (64 mg, 0.46 mmol), anddioxane/H₂O (2.5 mL/0.25 mL). The resulting solution was degassed withN₂ for 5 min and then sealed with a cap. The reaction was stirred at100° C. for 1 h in an oil bath. The resulting mixture was cooled to rt,diluted with EtOAc, and washed with 1N—HCl and brine. The organic layerwas dried with anhydrous Na₂SO₄ and concentrated. The residue waspurified from C18 reversed phase column chromatography eluting with 0.1%TFA-ACN/0.1% TFA-H₂O to afford methyl3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate(85 mg, 77%). LCMS (M+H)⁺: 472.3.

Step 11-3, preparation of3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid: to a solution of methyl3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylate(85 mg, 0.18 mmol) in MeOH/H₂O/THF (1/1/3 mL) was added lithiumhydroxide hydrate (108 mg, 15 eq.). The resulting solution was stirredat rt for 3 hrs. After removal of the volatile solvent, the aqueousresidue was diluted with H₂O (˜3 mL), and then acidified with 1N HCl.The resulting aqueous layer was extracted with DCM (3×). The combinedorganic layers were washed with brine, dried with with anhydrous Na₂SO₄,and concentrated under vacuum to afford3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid (75 mg, 91%). LCMS (M+H)⁺: 458.3.

Step 11-4, preparation of6-(2-ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazine-2-carboxylicacid: a solution of3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid (75 mg, 0.16 mmol) in TFA (0.2 mL)/DCM (0.6 mL) was stirred at rtfor 1.5 h. The resulting mixture was concentrated under vacuum. Theresidue (˜100%) was diluted with ACN (1 mL) and neutralized with Et₃N,which was used in the next step without further purification. LCMS(M+H)⁺: 358.2.

Step 11-5, preparation of3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid: to a solution of 4-chloro-2-(trifluoromethyl)benzoic acid (45 mg,0.2 mmol, 1.33 eq.) in ACN (1 mL) was added HATU (75 mg, 0.2 mmol) andfollowed by Et₃N (40 μL, 0.35 mmol). The resulting solution was stirredfor 5 min at rt and treated with6-(2-ethoxypyridin-3-yl)-3-[(2R)-2-ethylpiperazin-1-yl]pyrazine-2-carboxylicacid (˜55 mg, 0.15 mmol, 1 eq.) prepared from the previous step. Theresulting solution was stirred for 20 min at room temperature andconcentrated under vacuum. The residue was purified from C18 reversedphase column chromatography eluting with 0.1% TFA-ACN/0.1% TFA-H₂O toafford3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid (55 mg, 64%). LCMS (M+H)⁺: 564.5.

Step 11-6, preparation of tert-butylN-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate:to a 10-mL vial, was placed3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazine-2-carboxylicacid (30 mg, 0.053 mmol, 1.00 eq.), HATU (21 mg, 0.056 mmol), Et₃N (11μL, 0.08 mmol) and ACN (1 mL). The resulting solution was stirred for 5min at rt and treated with tert-butyl N-(2-aminoethyl)-N-methylcarbamate(11 mg, 0.063 mmol, 1.2 eq.). The reaction was stirred for 20 min atroom temperature and concentrated under vacuum. The residue was purifiedfrom C18 reversed phase column chromatography eluting with 0.1%TFA-ACN/0.1% TFA-H₂O to afford tert-butylN-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate(18 mg, 47%). LCMS (M+H)⁺: 720.3.

Step 11-7, preparation of3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide:a solution of tert-butylN-[2-({3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)pyrazin-2-yl}formamido)ethyl]-N-methylcarbamate(18 mg, 0.025 mmol) in TFA (0.2 mL)/DCM (0.6 mL) was stirred at rt for1.5 h. The resulting mixture was concentrated under vacuum. The residuewas purified from C18 reversed phase column chromatography eluting with0.1% TFA-ACN/0.1% TFA-H₂O to afford3-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxypyridin-3-yl)-N-[2-(methylamino)ethyl]pyrazine-2-carboxamide(10 mg, 67%). LCMS (M+H)⁺: 620.4.

The following compounds were prepared similarly to Example 11 withappropriate substituting reagents and substrates at different steps. Insome examples, an additional deprotection is not required in the finalstep.

Compound MS no. (M + H)⁺ 3-7 634.2

Example 12:1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine(Compound 2-13)

Step 12-1, preparation of1-{5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridin]-6-yl}methanamine:to a solution of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrilefrom Example 9, step 9-4 (65 mg, 0.12 mmol) in MeOH (1.0 mL) was addedNiCl₂ (8.0 mg, 0.06 mmol, 0.5 eq.) and NaBH₄ (36 mg, 0.96 mmol, 8.0 eq.)at 0° C. The resulting mixture was stirred at the same temperature for15 min and LCMS analysis showed about 40% conversion to the desiredproduct. At 0° C., an additional NiCl₂ (0.5 equiv, 0.06 mmol, 8.0 mg)and NaBH₄ (8.0 equiv, 0.96 mmol, 36 mg) were added and the resultingmixture was stirred for another 15 min. The reaction mixture was dilutedwith ethyl acetate and washed with saturated NH₄Cl. The organic layerwas dried and concentrated. The residue was purified by a C18reversed-phase column chromatography eluting with MeCN/water (5-60%).Pure fractions were combined, neutralized with saturated NaHCO₃ andNaCl, extracted with ethyl acetate and dried with MgSO₄. The organiclayer was concentrated and dried under high vacuum to give 8 mg (12%) ofthe desired product. LCMS (M+H)⁺=548.3.

The following compounds were prepared similarly to Example 12 withappropriate substituting reagents and substrates at different steps.Some examples may require additional functional group transformations tointroduce an appropriate substituent on aryl rings.

Compound no. MS (M + H)⁺ 2-3  532.2 2-4  576.4 2-5  560.2 2-6  562.42-7  528.2 2-8  532.2 2-9  547.3 2-10 568.5 2-11 515.3 2-12 547.3 2-14494.3 2-15 548.2 2-16 562.3 2-17 498.2 2-18 515.3 2-19 500.3 2-20 531.92-22 532.1 2-23 546.3 2-24 572.3 2-25 558.1 2-26 544.3 2-27 526.3 2-28544.3 2-29 544.4

Example 13:2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-ol(Compound 2-1)

Step 13-1, preparation of tert-butyl(3R)-4-[2′-ethoxy-3-(methoxycarbonyl)-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylateinto a 8-mL pressure tube vessel, was placed tert-butyl(3R)-4-[4-bromo-2-(methoxycarbonyl)phenyl]-3-ethylpiperazine-1-carboxylatefrom Example 1, step 1.3 (80 mg, 0.19 mmol), (2-ethoxyphenyl)boronicacid (46.6 mg, 0.28 mmol), Pd₂(dba)₃CHCl₃ (19.4 mg, 0.02 mmol),P(t-Bu)₃.HBF₄ (5.4 mg, 0.02 mmol), K₃PO₄ (119.2 mg, 0.56 mmol), andtoluene/H₂O (1 mL/0.1 mL). The resulting solution was degassed for 5 minwith N₂, sealed, and stirred at 70° C. for 2 hrs in an oil bath. Thereaction was cooled to rt and concentrated under vacuum. The residue wasapplied onto a silica gel column eluting with ethyl acetate/petroleumether (1:1). 80 mg (91%) of the desired product was isolated. LCMS(M+H)⁺=469.1.

Step 13-2, preparation of tert-butyl(3R)-4-[2′-ethoxy-3-(hydroxymethyl)-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate:to a heterogenous solution of tert-butyl(3R)-4-[2′-ethoxy-3-(hydroxymethyl)-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate(60 mg, 0.13 mmol) and NiCl₂ (16.6 mg, 0.13 mmol) in MeOH (1.0 mL) wasadded NaBH₄ (48.4 mg, 1.28 mmol, 10 eq.) at rt. The resulting mixturewas stirred at 50° C. for 1 h. The reaction mixture was cooled to rt,diluted with H₂O, and extracted with ethyl acetate (3×). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated toafford 60 mg (˜100%) of the desired product. LCMS (M+H)⁺=441.3.

Step 13-3, preparation of tert-butyl(3R)-4-{2′-ethoxy-3-formyl-[1,1′-biphenyl]-4-yl}-3-ethylpiperazine-1-carboxylate:a solution of tert-butyl(3R)-4-[2′-ethoxy-3-(hydroxymethyl)-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate(90 mg, 0.2 mmol) and IBX (171.6 mg, 0.62 mmol) in ACN (2 mL) wasstirred at rt for 1 h. After removal of the solids by filtration, thefiltrate was concentrated under vacuum to afford the crude desiredproduct (90 mg, ˜100%), which was used in the next strip without furtherpurification. LCMS (M+H)⁺=439.3.

Step 13-4, preparation of tert-butyl(3R)-4-[3-({[2-(benzyloxy)ethyl]amino}methyl)-2′-ethoxy-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate:to a solution of tert-butyl(3R)-4-{2′-ethoxy-3-formyl-[1,1′-biphenyl]-4-yl}-3-ethylpiperazine-1-carboxylate(30 mg, 0.07 mmol) and 2-(benzyloxy)ethan-1-amine (21 mg, 0.14 mmol) inDCM (2.0 mL) was added NaBH(OAc)₃ (44 mg, 0.21 mmol, 3 eq.). Theresulting mixture was stirred at rt for 30 min and diluted with H₂O (20mL). The resulting solution was extracted with EtOAc (3×). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated toafford the desired product (25 mg, 64%). LCMS (M+H)⁺=574.4.

Step 13-5, preparation of[2-(benzyloxy)ethyl]({2′-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-yl}methyl)aminetrifluoroacetate: to a solution of tert-butyl(3R)-4-[3-({[2-(benzyloxy)ethyl]amino}methyl)-2′-ethoxy-[1,1′-biphenyl]-4-yl]-3-ethylpiperazine-1-carboxylate(25 mg, 0.04 mmol) in DCM (2.0 mL) was added TFA (1 mL). The resultingmixture was stirred at rt for 1 h and and concentrated under vacuum.This resulted in the desired product (25 mg, 98%) as TFA salt. LCMS(M+H)⁺=474.3.

Step 13-6, preparation of[2-(benzyloxy)ethyl]({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amine:to a solution of 2-chloro-4-(trifluoromethyl)benzoic acid (2 mg, 0.01mmol, 0.3 eq.), HATU (5.7 mg, 0.01 mmol. 0.3 eq.) and[2-(benzyloxy)ethyl]({2′-ethoxy-4-[(2R)-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-yl}methyl)aminetrifluoroacetate (17.5 mg, 0.03 mmol) in DMF (2 mL) was added DIEA (11.6mg, 0.09 mmol, 3 eq.). The resulting mixture was stirred at rt for 1 hand diluted with H₂O (20 mL). The resulting solution was extracted withEtOAc (3×). The combined organic layers were dried over anhydrous Na₂SO₄and concentrated. The residue was purified by a silica gel columnchromatography eluting with DCM/MeOH (10/1) to afford the desiredproduct (20 mg, 38%). LCMS (M+H)⁺=680.2.

Step 13-7, preparation of2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-oltrifluoroacetate: A solution of[2-(benzyloxy)ethyl]({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amine(20 mg, 0.03 mmol) in TFA (1.0 mL) was stirred at 80° C. for 3 hrs. Theresulting mixture was cooled to rt and and concentrated under vacuum.The residue was purified by Prep-HPLC with the following conditions:SunFire Prep C18 OBD column; mobile phase, phase A: water (0.05% TFA);phase B: ACN (31% up to 45% in 6 min); flow rate: 20 mL/min; detector,220 & 254 nm. 3.9 mg (19%) of the desired product was isolated as a TFAsalt. LCMS (M+H)⁺=590.2.

The following compounds were prepared similarly to Example 13 withappropriate substituting reagents and substrates at different steps. Insome examples, an additional deprotection is not required in the finalstep.

Compound no. MS (M + H)⁺ 2-2  604.3 2-21 588.4

Example 14:N-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide(Compound 3-2)

Step 14-1, preparation of tert-butyl4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazine-1-carboxylate: to asolution of tert-butyl piperazine-1-carboxylate (1.600 g, 8.588 mmol)and methyl 4-bromo-2-fluorobenzoate (1.000 g, 4.292 mmol) in DMSO (5 mL)was added DIEA (2.20 mL, 12.6 mmol). The mixture was heated at 130° C.for 1 day. The mixture was distributed between water and DCM and theorganic layer was separated and concentrated. The residue was purifiedby C18 reversed phase column chromatography to give the title compound(0.5088 g, 30% yield) as a medium brown solid. MS (M+H)⁺: 399.2. Thehydrolyzed acid (0.7537 g, 46% yield) was also isolated as a light brownsolid. LCMS (M+H)⁺=385.3.

Step 14-2, preparation of methyl 5-bromo-2-(piperazin-1-yl)benzoatehydrochloride: to a solution of tert-butyl4-[4-bromo-2-(methoxycarbonyl)phenyl]piperazine-1-carboxylate (508.8 mg,1.274 mmol) in DCM (2 mL) was added 4N HCl in dioxane (2.0 mL, 8.0mmol). The mixture was stirred at rt for 2 hrs. The mixture wasconcentrated to dryness to give the title compound as a light yellowsolid. LCMS (M+H)⁺=299.2.

Step 14-3, preparation of methyl5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoate:To a solution of methyl 5-bromo-2-(piperazin-1-yl)benzoate hydrochloride(0.4538 g, 1.352 mmol) and 2-fluoro-5-(trifluoromethyl)benzonitrile(353.0 mg, 1.867 mmol) in DMSO (3 mL) was added DIEA (0.81 mL, 4.7mmol). The mixture was heated at 130° C. overnight. The mixture waspurified by C18 reversed phase column chromatography to give the titlecompound (453 mg, 72% yield) as a yellow solid. LCMS (M+H)⁺=468.3.

Step 14-4, preparation of5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoicacid: To a solution of methyl5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoate(453 mg, 0.967 mmol) in a mixed solvent of THF:MeOH:H₂O (6:2:2 mL) wasadded LiOH.H₂O (406 mg, 9.67 mmol). The mixture was stirred at rt for 4hrs. After removal of volatile solvent, the aqueous residue was dilutedwith water and acidified with 1N HCl (aq) to pH 2-3. The solid wascollected by vacuum filtration and washed with water and dried to givetitle compound (421 mg, 96% yield) as a yellow solid. LCMS (M+H)⁺=454.1.

Step 14-5, preparation of tert-butylN-{3-[(5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)formamido]propyl}carbamate:To a solution of5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}benzoicacid (201.9 mg, 0.4444 mmol) and HATU (220 mg, 0.579 mmol) in DMF (1 mL)was added DIEA (0.15 mL, 0.86 mmol). After stirring at RT for 5 min, theresulting solution was treated with tert-butylN-(3-aminopropyl)carbamate (126.5 mg, 0.7262 mmol) and stirred at rt for5 min. The reaction was purified by C18 reversed phase columnchromatography to give the title compound (198.7 mg, 73% yield) as anoff-white solid. LCMS (M+H)⁺=610.3.

Step 14-6, preparation of tert-butylN-{3-[(4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-yl)formamido]propyl}carbamate:To a mixture of tert-butylN-{3-[(5-bromo-2-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}phenyl)formamido]propyl}carbamate(20.0 mg, 0.0328 mmol), 2-ethoxyphenylboronic acid (10.9 mg, 0.0657mmol), Pd[t-Bu₂P(4-NMe₂C₆H₄)]₂Cl₂) (9.2 mg, 0.013 mmol), and K₂CO₃ (27.2mg, 0.197 mmol) in a sealed tube was added dioxane (2 mL) and H₂O (0.2mL). The resulting mixture was degassed with N₂ for 10 min and stirredat 100° C. for 30 min. The mixture was concentrated and purified by C18reversed phase column chromatography to give the title compound (18.5mg, 87% yield) as a white solid. LCMS (M+H)⁺=652.5.

Step 14-7, preparation ofN-(3-aminopropyl)-4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide:to a solution of tert-butylN-{3-[(4-{4-[2-cyano-4-(trifluoromethyl)phenyl]piperazin-1-yl}-2′-ethoxy-[1,1′-biphenyl]-3-yl)formamido]propyl}carbamate(18.5 mg, 0.0284 mmol) in DCM (0.1 mL) was added 4N HCl in dioxane (0.1mL, 0.4 mmol). The mixture was stirred at rt for 30 min. The mixture wasconcentrated to dryness to give 1HCl salt of the title compound whichwas triturated with saturated NaHCO₃ (aq) to give the title compound(12.9 mg, 82% yield) as an off-white solid. LCMS (M+H)⁺=552.2.

The following compounds were prepared similarly to Example 14 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 3-1 544.3

Example 15:6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylamino)ethyl]benzamide(Compound 3-3)

Step 15-1, preparation of benzylN-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate:into a 8-mL vial, was placed benzylN-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorophenyl]formamido]ethyl)-N-methylcarbamatetrifluoroacetate (30 mg, 0.027 mmol), which was prepared by a similarmanner described in Example 4, step 1 & 2, TEA (8 mg, 0.079 mmol, 2.98eq.), 2,4-dichlorobenzene-1-sulfonyl chloride (8 mg, 0.033 mmol, 1.23eq.), and DCM (2 mL). The resulting solution was stirred for 2 hr at 25°C. The reaction was diluted with DCM (10 mL) and washed with H₂O (2×20mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 20 mg (crude) of the titlecompound as off-white oil. LCMS (M+H)⁺=772.2.

Step 15-2, preparation of6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluoro-N-[2-(methylaminoethyl]benzamide:Into a 8-mL vial, was placed benzylN-[2-([6-[(2R)-4-(2,4-dichlorobenzenesulfonyl)-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate(20 mg, 0.021 mmol) and trifluoroacetic acid (2 mL). The resultingsolution was stirred for 3 hrs at 60° C., cooled to rt, and concentratedunder vacuum. The residue was dissolved in DMF (4 mL) and purified byreverse phase HPLC resulting in 7.9 mg (56%) of the title compound as aformic acid salt. LCMS (M+H)⁺=638.2

Example 16:(3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-{[2-(methylamino)ethyl]carbamoyl}phenyl]-3-ethylpiperazine-1-carboxamide(Compound 3-4)

Step 16-1, preparation of phenyl N-(2,4-dichlorophenyl)carbamate: Into a8-mL vial, was placed 2,4-dichloroaniline (200 mg, 1.23 mmol) and THE (5mL). The resulting solution was treated with NaH (59 mg, 1.47 mmol, 1.19eq, 60% purity) and stirred for 20 min at 0° C. The reaction was treatedwith phenyl carbonochloridate (232 mg, 1.48 mmol, 1.2 eq.), stirred foran additional 3 hr at 0° C., and concentrated under vacuum. The residuewas purified from a silica gel column chromatography eluting with ethylacetate/petroleum ether (1:5). This resulted in 120 mg (34%) of thetitle compound as yellow oil. LCMS (M+H)⁺=282.0.

Step 16-2, preparation of benzylN-[2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate:Into a 8-mL vial, was placed benzylN-(2-[[3-(2-ethoxypyridin-3-yl)-6-[(2R)-2-ethylpiperazin-1-yl]-2-fluorophenyl]formamido]ethyl)-N-methylcarbamatetrifluoroacetate (36 mg, 0.053 mmol), DCM (2 mL), TEA (16 mg, 0.158mmol, 2.97 eq.), and phenyl N-(2,4-dichlorophenyl)carbamate (15 mg,0.053 mmol). The resulting solution was stirred for 2 hrs at 25° C.,diluted with DCM (10 mL), and washed with water (2×20 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated undervacuum. This resulted in 30 mg (crude) of the title compound as yellowoil. LCMS (M+H)⁺=751.2.

Step 16-3, preparation of(3R)—N-(2,4-dichlorophenyl)-4-[4-(2-ethoxypyridin-3-yl)-3-fluoro-2-[[2-(methylamino)ethyl]carbamoyl]phenyl]-3-ethylpiperazine-1-carboxamide:Into a 8-mL vial, was placed benzylN-[2-([6-[(2R)-4-[(2,4-dichlorophenyl)carbamoyl]-2-ethylpiperazin-1-yl]-3-(2-ethoxypyridin-3-yl)-2-fluorophenyl]formamido)ethyl]-N-methylcarbamate(30 mg, 0.04 mmol) and TFA (2 mL). The resulting solution was stirredfor 2 hrs at 60° C., cooled to rt, and concentrated under vacuum. Theresidue was dissolved in DMF (4 mL) and purified by Prep-HPLC with thefollowing conditions (Prep-HPLC-013): Column, Atlantis Prep T3 OBDColumn, 19*150 mm Sum; mobile phase, Water (0.1% FA) and ACN (24% PhaseBup to 53% in 6 min); 20 mL/min. Detector, UV 220, 254 nm. This resultedin 5.6 mg (21%) of the title compound as a formic acid salt. LCMS(M+H)⁺=617.2.

Example 17:5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-152)

Step 17-1, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid from Example 9, step 5 (40 mg, 0.071 mmol) in ACN (0.5 mL) wasadded HATU (30 mg, 0.078 mmol, 1.1 eq.) and Et₃N (19 μL, 2.0 eq.). Theresulting solution was stirred at rt for 5 min and treated with(R)-1-methylpyrrolidin-3-ylamine (10.6 mg, 0.106 mmol, 1.5 eq.). Thereaction was stirred at rt for 0.5 h. The crude reaction solution waspurified by a C18 reversed phase column chromatography eluting withMeCN/water (5-100%). The combined pure fractions were neutralized withsaturated NaHCO₃, removed volatile solvent, and extracted with DCM (3×).The combined organic layer was dried with anhydrous Na₂SO₄, concentratedand dried under high vacuum to give 25 mg (55%) of the title compound.LCMS (M+H)⁺=645.5.

Example 18:5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide(Compound 1-212)

Step 18-1, preparation of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-(1-methylazetidin-3-yl)-[2,3′-bipyridine]-6-carboxamide:the title compound was prepared by a similar manner described in Example17 starting from 40 mg (0.071 mmol) of5-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid. 20 mg (45%) of the title compound was isolated. LCMS (M+H)⁺=631.4.

The following compounds were prepared similarly to Example 18 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 1-359 663.3 1-398 671.4

Example 19:1-{2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine(Compound 2-30)

Step 19-1, preparation of5-[(2R)-4-[6-chloro-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile:to a DMF (3.0 mL) of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitrile(Step 9-3, 1.0 equiv, 0.26 mmol, 87 mg) was added DIPEA (2.5 equiv, 0.65mmol, 0.1 mL), HATU (1.2 equiv, 0.39 mmol, 118 mg) and6-chloro-2-(trifluoromethyl)pyridine-3-carboxylic acid (1.0 equiv, 0.26mmol, 61 mg). The resulting mixture was stirred at rt for 0.5 h and LCMSshowed complete consumption of starting material. The reaction solutionwas diluted with ethyl acetate (50 mL), washed with water and brine,dried with anhydrous Na₂SO₄, filtered and concentrated. The remainingresidue was purified by silica gel chromatography eluting withEtOAc/hexane (0-50%) to afford 104 mg of the title compound. LCMS(M+H)⁺=545.3.

Step 19-2, preparation of2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitrile:to an EtOH (0.5 mL) solution of5-[(2R)-4-[6-chloro-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carbonitrile(1.0 equiv, 0.05 mmol, 28 mg) was added NaOEt (21% w/w in EtOH, 2.5equiv, 0.13 mmol, 0.05 mL). The resulting mixture was heated at 70° C.for 0.5 h. The reaction solution was diluted with ethyl acetate (20 mL),washed with saturated NH₄Cl and brine, dried with anhydrous Na₂SO₄,filtered and concentrated to afford 25 mg of crude product. Thismaterial was used for next step without purification. LCMS (M+H)⁺=555.2.

Step 19-3, preparation of tert-butylN-({2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methyl)carbamate:to a MeOH (1.0 mL) solution of2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-carbonitrile(1.0 equiv, 0.05 mmol, 25 mg) was added NiCl₂ (0.5 equiv, 0.025 mmol,3.3 mg) and di-tert-butyl dicarbonate (2.0 equiv, 0.10 mmol, 0.023 mL).At 0° C., NaBH₄ (7.0 equiv, 0.35 mmol, 13.5 mg) was added portion-wiseand the resulting mixture was stirred at the same temperature for 0.5 h.The reaction mixture was filtered and filtrate was concentrated. Theremaining residue was purified by silica gel chromatography eluting withEtOAc/hexane (0-50%) to afford 24 mg of the title compound. LCMS(M+H)⁺=659.4.

Step 19-4, preparation of1-{2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methanamine:to a DCM (0.5 mL) of tert-butylN-({2′-ethoxy-5-[(2R)-4-[6-ethoxy-2-(trifluoromethyl)pyridine-3-carbonyl]-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-yl}methyl)carbamate(1.0 equiv, 0.036 mmol, 24 mg) was added TFA (0.10 mL). The resultingmixture was stirred at ambient temperature for 0.5 h. The reactionsolution was concentrated and the residue obtained was purified by C18reversed-phase chromatography eluting with MeCN/water (5-50%). Purefractions were combined, neutralized with saturated NaHCO₃ and NaCl,extracted with ethyl acetate and dried with MgSO₄. The organic layer wasconcentrated and dried under high vacuum to give 6 mg of the titlecompound. LCMS (M+H)⁺=559.2

The following compounds were prepared similarly to Example 19 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 2-31 545.4

Example 20:5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-279)

Step 20-1, preparation of 2-(difluoromethyl)-4-fluorobenzoic acid: to amixture of 4-fluoro-2-methylbenzoic acid (1.000 g, 6.49 mmol),Selectfluor (6.895 g, 19.46 mmol) and sodium persulfate (0.772 g, 3.24mmol) under nitrogen was added MeCN (3.2 mL) and water (3.2 mL). Themixture was cooled to −78° C. under nitrogen and silver nitrate (110.2mg, 0.649 mmol) was added. The frozen mixture was degassed under vacuumand charged with nitrogen (repeated 3×). The mixture was warmed to rtunder nitrogen and then heated at 80° C. for 7 hrs. The reaction was notcomplete and thus more Selectfluor (2.298 g, 6.49 mmol), sodiumpersulfate (0.257 g, 1.08 mmol) and silver nitrate (36.7 mg, 0.216 mmol)were added under nitrogen and the reaction was continued to heat at 80°C. for 6 hrs. The mixture was filtered through Celite and rinsed withEtOAc. The filtrate was washed with saturated NaHCO₃ (aq) (5×25 mL). Thecombined basic aqueous solution was acidified with 1N HCl (aq) to pH 2-3to form a solid. The solid was collected by vacuum filtration, washedwith water and dried under vacuum to give the title compound (484.1 mg).The filtrate was extracted with EtOAc (1×) and the organic layer wasconcentrated and purified by C18 reversed phase column chromatography togive more product (314.4 mg). The reaction overall gave the titlecompound (798.5 mg, 4.20 mmol, 64.7% yield) as an off-white solid.

Step 20-2, preparation of tert-butyl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate:to a solution of5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid (400 mg, 0.876 mmol) from Step 10-1 in DMF (2.0 mL) was added HATU(500 mg, 1.31 mmol), DIEA (0.46 mL, 2.63 mmol). After stirring at rt for5 min, (3R)-1-methylpyrrolidin-3-amine (176 mg, 1.75 mmol) was added.The resulting mixture was stirred at rt for 10 min. The reaction mixturewas purified by C18 reversed phase column chromatography to give thetitle compound (284.6 mg, 0.53 mmol, 60.3% yield) as a light brownsolid. LCMS (M+H)⁺=539.5.

Step 20-3, preparation of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidetris(2,2,2-trifluoroacetate): to a solution of tert-butyl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(268.8 mg, 0.50 mmol) in DCM (1.5 mL) was added TFA (0.76 mL). Theresulting mixture was stirred at rt for 30 min and concentrated in vacuoto dryness to give the title compound (389.5 mg, 0.50 mmol, 100% yield)as a brown gum which was used in the next step without furtherpurification. LCMS (M+H)⁺=439.1.

Step 20-4, preparation of5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of 2-(difluoromethyl)-4-fluorobenzoic acid (142.3 mg, 0.75mmol) in DMF (0.5 mL) was added HATU (265.6 mg, 0.70 mmol) and DIEA(0.26 mL, 1.50 mmol). After stirring at rt for 5 min, thisHATU-activated solution was added to a solution of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidetris(2,2,2-trifluoroacetate) (389.5 mg, 0.50 mmol) and DIEA (0.52 mL,3.00 mmol) in DMF (0.5 mL). The resulting mixture was stirred at rt for10 min. The reaction mixture was purified by C18 reversed phase columnchromatography to give the title compound (245.0 mg, 0.40 mmol, 80.4%yield) as a light brown solid. LCMS (M+H)⁺=611.3.

The following compounds were prepared similarly to Example 20 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 1-262 627.3 1-287 626.5 1-293 610.4

Example 21:5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-278)

Step 21-1, preparation of tert-butyl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate:to a solution of5-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-carboxylicacid (300 mg, 0.657 mmol) from Step 10-1 in DMF (1.0 mL) was added HATU(325 mg, 0.854 mmol), DIEA (0.23 mL, 1.3 mmol). After stirring at rt for5 min, benzyl (3R)-3-aminopyrrolidine-1-carboxylate (217 mg, 0.986 mmol)was added. The resulting mixture was stirred at rt for 10 min. Thereaction mixture was purified by C18 reversed phase columnchromatography to give the title compound (270.8 mg, 0.411 mmol, 62.6%yield) as a brown solid. LCMS (M+H)⁺=659.5.

Step 21-2, preparation of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylatebis(2,2,2-trifluoroacetate): to a solution of tert-butyl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(90.0 mg, 0.137 mmol) in DCM (0.4 mL) was added TFA (0.2 mL). Theresulting mixture was stirred at rt for 30 min and concentrated in vacuoto dryness to give the title compound (107 mg, 0.137 mmol, 100% yield)as a brown gum which was used in the next step without furtherpurification. LCMS (M+H)⁺=559.4.

Step 21-3, preparation of benzyl(3R)-3{5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylate:to a solution of 2-(difluoromethyl)-4-fluorobenzoic acid (38.8 mg, 0.204mmol) from Step 20-1 in DMF (0.2 mL) was added HATU (72.4 mg, 0.190mmol) and DIEA (0.071 mL, 0.41 mmol). After stirring at rt for 5 min,this HATU-activated solution was added to a solution of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylatebis(2,2,2-trifluoroacetate) (107 mg, 0.136 mmol) and DIEA (0.14 mL, 0.80mmol) in DMF (0.2 mL). The resulting mixture was stirred at rt for 10min. The reaction mixture was purified by C18 reversed phase columnchromatography to give the title compound (63.0 mg, 0.0862 mmol, 63.4%yield) as a light yellow solid. LCMS (M+H)⁺=731.3.

Step 21-4, preparation of5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to benzyl(3R)-3{5-[(2R)-4-[2-(difluoromethyl)-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylate(63.0 mg, 0.0862 mmol) was added (methylsulfanyl)benzene (0.050 mL) andTFA (0.25 mL). The resulting mixture was heated at 60° C. for 30 min.The reaction mixture was purified by C18 reversed phase columnchromatography to give the title compound (39.9 mg, 0.0669 mmol, 77.6%yield) as an off-white solid. LCMS (M+H)⁺=597.4.

The following compounds were prepared similarly to Example 21 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 1-265 613.3 1-288 612.1 1-292 596.4

Example 22:2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-263)

Step 22-1, preparation of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylate:to a solution of tert-butyl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylatefrom Example 21, step 1 (27 mg, 0.041 mmol) in DCM (0.4 mL) was addedTFA (0.1 mL). The resulting solution was stirred at rt for 1 h andconcentrated under vacuum to remove the volatile solvent. The residuewas dissolved in ACN (0.3 mL) and neutralized with TEA (16 μL, ˜3 eq.),which was used in the next step without further purification. LCMS(M+H)⁺=559.3.

Step 22-2, preparation of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylate:to a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (11mg, 0.06 mmol) in ACN (0.5 mL) was added HATU (22 mg, 0.06 mmol) and TEA(11 μL, 0.08 mmol). After stirring at rt for 5 min, the resultingsolution was treated with benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylatefrom step 1 (22 mg, 0.039 mmol). The reaction was stirred at rt for 30min and directly purified by C18 reversed phase column chromatography togive the title compound (21 mg, 74% yield). LCMS (M+H)⁺=723.8.

Step 22-3, preparation of2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-[2,3′-bipyridine]-6-amido}pyrrolidine-1-carboxylate(21 mg, 0.029 mmol) in TFA (0.5 mL) was added one drop ofmethyl(phenyl)sulfane. The resulting mixture was stirred at 60° C. for 1hr and cooled to rt. After removal of the volatile solvent, the residuewas purified by C18 reversed phase column chromatography to give thetitle compound (14 mg, 82% yield) as a white powder. LCMS (M+H)⁺=589.4.

The following compounds were prepared similarly to Example 22 withappropriate substituting reagents and substrates at different steps:

Compound no. MS (M + H)⁺ 1-250 523.6 1-251 608.3 1-252 608.3 1-264 537.61-273 603.5 1-274 629.5 1-280 575.5 1-285 641.4 1-294 613.4 1-295 593.41-297 615.5 1-298 611.3 1-299 603.3 1-300 575.3 1-301 575.3 1-302 563.31-304 588.4 1-308 577.6 1-314 575.5 1-318 607.5 1-321 589.3 1-324 603.51-325 603.5 1-327 589.3 1-328 571.4 1-329 589.4 1-335 602.5 1-352 597.41-353 583.4 1-354 611.4 1-368 603.3

Example 23:2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-255)

Step 23-1, preparation of2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of 1-(trifluoromethyl)cyclopentane-1-carboxylic acid (13mg, 0.071 mmol) in ACN (0.5 mL) was added HATU (27 mg, 0.071 mmol) andTEA (19 μL, 0.14 mmol). After stirring at rt for 5 min, the resultingsolution was treated with neutral2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidefrom Example 20, step 3 (20 mg, 0.045 mmol). The reaction was stirred atrt for 30 min and directly purified by C18 reversed phase columnchromatography to give the title compound (19 mg, 70% yield). LCMS(M+H)⁺=603.6.

The following compounds were prepared similarly to Example 23 withappropriate substituting reagents and substrates at different steps.Some examples may require a reductive amination to introduce thetert-amine moeity in the final step:

Compound no. MS (M + H)⁺ 1-235 561.4 1-238 587.3 1-241 589.5 1-248 571.51-281 629.5 1-282 643.5 1-284 655.4 1-286 617.6 1-313 603.6 1-319 621.51-322 617.4 1-330 603.5 1-331 603.5 1-332 617.5 1-333 617.6 1-334 633.41-336 616.6 1-337 603.6 1-339 629.4 1-340 602.6 1-341 602.4 1-359 617.41-363 603.4 1-378 617.2 1-379 601.4 1-380 617.3 1-382 617.5 1-385 629.51-388 628.5 1-394 615.4 1-395 629.5 1-399 588.4 1-400 629.5 1-401 602.41-405 615.5 1-415 616.4 1-416 585.3 1-417 584.4

Example 24:2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-283)

Step 24-1, preparation of2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (632mg, 3.76 mmol) in DMF (5.0 mL) was added HATU (1.43 g, 3.76 mmol) andTEA (0.67 mL, 5.02 mmol). After stirring at rt for 5 min, the resultingsolution was treated with2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidefrom Example 20, step 3 (1.10 g, 2.51 mmol). The reaction was stirred atrt for 30 min and directly purified by C18 reversed phase columnchromatography to give the title compound (0.85 g, 58% yield). LCMS(M+H)⁺=589.4.

The following compounds were prepared similarly to Example 24 withappropriate substituting reagents and substrates at different steps.Some examples may require a reductive amination to introduce thetert-amine moeity in the final step:

Compound no. MS (M + H)⁺ 1-344 588.4 1-349 602.5 1-358 597.2 1-364 589.41-371 633.4 1-390 589.4 1-411 615.4

Example 25:6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamide(Compound 1-374)

Step 25-1, preparation of tert-butyl(3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate:Into a 1000-mL round-bottom flask, was placed6-bromo-3-fluoropicolinonitrile (50.0 g, 249 mmol), tert-butyl(R)-3-ethylpiperazine-1-carboxylate (59 g, 275 mmol), DIEA (97 g, 750mmol), and DMSO (500 mL). The resulting reaction mixture was stirred for24 hrs at 90° C. The reaction mixture was cooled to room temperature andquenched with water (1000 mL). The resulting solution was extracted withethyl acetate (3×1000 mL). The organic layers were dried over anhydroussodium sulfate and concentrated under vacuum. This resulted in the titlecompound (100 g, 66%) as a yellow oil. LCMS (M+H)⁺=395.1.

Step 25-2, preparation of tert-butyl(3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3-ethylpiperazine-1-carboxylate:Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed tert-butyl(3R)-4-(6-bromo-2-cyanopyridin-3-yl)-3-ethylpiperazine-1-carboxylate(5.0 g, 13 mmol), (2-ethoxyphenyl)boronic acid (4.0 g, 26 mmol),potassium carbonate (5.0 g, 36 mmol), Pd(DtBPF)Cl₂ (0.4 g, 0.62 mmol),and dioxane/water (50 mL/5 mL). The resulting solution was stirred at80° C. for 1 hour and cooled to rt. The inorganic solid was filteredoff, and the filtrate was concentrated. The residue was purified from asilica gel column eluting with ethyl acetate/petroleum ether (1:3). Thisresulted in the title compound (4.0 g, 67%) as a yellowish oil. LCMS(M+H)⁺=437.2.

Step 25-3, preparation of3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylicacid: Into a 250-mL round-bottom flask purged, was placed tert-butyl(3R)-4-[2-cyano-6-(2-ethoxyphenyl)pyridin-3-yl]-3-ethylpiperazine-1-carboxylate(4.0 g, 9.2 mmol), EtOH (40 mL), and water (40 mL). This resultingsolution was treated with KOH (5.3 g, 94 mmol) at rt and then stirred at100° C. for 50 hrs. The reaction was cooled to rt and concentrated toremove EtOH. The pH of aqueous layer was adjusted to 6-7 with 3N—HCl.The resulting solution was extracted with ethyl acetate (3×50 mL). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, and concentrated to afford the title compound (2.3 g,55%) as a yellow solid. LCMS (M+H)⁺=456.2.

Step 25-4, preparation of ethyl6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylate:Into a 50-mL round-bottom flask, was placed3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylicacid (1.0 g, 2.2 mmol), EtOH (10 mL), and sulfuric acid (0.5 mL). Theresulting reaction mixture was stirred at 80° C. for 3 hours and cooledto rt. The reaction was diluted with water (50 ml) and then adjusted topH 6-7 with sodium bicarbonate. The resulting solution was extractedwith EtOAc (3×10 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated undervacuum to afford the title compound (400 mg, 48%) as a yellow oil. LCMS(M+H)⁺=384.2.

Step 25-5, preparation of ethyl6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylate:Into a 8-mL vial, was placed (S)-2-(trifluoromethyl)pyrrolidine (75 mg,0.54 mmol), DIEA (210 mg, 1.62 mmol), and DCM (1 mL). The reactionmixture was cooled to 0° C. and treated with bis(trichloromethyl)carbonate (64 mg, 0.22 mmol). The resulting mixture was stirred at 0° C.for 3 hours, quenched with water (20 mL), and extracted with DCM (3×20mL). The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under vacuum. The activated pyrrolidine wasused in the next step directly without further purification. Ethyl6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylate(210 mg, 5.43 mmol), the activated pyrrolidine described above, andpotassium carbonate (750 mg, 5.43 mmol), and ACN (2 mL) were placed intoa 8-mL vial. The resulting reaction mixture was stirred at 30° C. for 2hours and cooled to room temperature. The crude product was purified bya reverse phase C18 column chromatography to afford the title compound(200 mg, 68%) as a yellow oil. LCMS (M+H)⁺=549.4.

Step 25-6, preparation of6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylicacid: Into a 8-mL vial, was placed ethyl6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylate(200 mg, 0.365 mmol), LiOH (88 mg, 3.7 mmol), EtOH (2 mL), and water (1mL). The resulting reaction mixture was stirred at 60° C. for 1 h andcooled to rt. The reaction was diluted with water (10 ml), and thenadjusted to pH 6-7 with 3N—HCl. The resulting solution was extractedwith EtOAc (3×10 mL). The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated to affordthe title compound (170 mg, 90%) as a yellow oil. LCMS (M+H)⁺=521.6.

Step 25-7, preparation of6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]pyridine-2-carboxamideformate: Into a 50-mL round-bottom flask, was placed6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[(2S)-2-(trifluoromethyl)pyrrolidine-1-carbonyl]piperazin-1-yl]pyridine-2-carboxylicacid (80 mg, 0.15 mmol), HATU (58 mg, 0.15 mmol), DIEA (40 mg, 0.30mmol), and DMF (1 mL). The resulting reaction mixture was stirred for 10min at rt, and then treated with (R)-1-methylpyrrolidin-3-amine (20 mg,0.20 mmol). The resulting reaction mixture was stirred at rt for 1 h.The crude product was purified by Prep-HPLC with the followingconditions (Prep-HPLC-013): Column, Atlantis Prep T3 OBD Column, 19*150mm Sum; mobile phase, Water (0.1% FA) and ACN (30% Phase B up to 90% in8 min); Total flow 20 mL/min. Detector, UV 220 nm. This resulted in thetitle compound (62 mg, 62%) as a white solid. LCMS (M+H)⁺=603.4.

The following compounds were prepared similarly to Example 25 withappropriate substituting reagents and substrates at different steps.Some examples may require a chiral separation to get optically purecompounds, but their absolute stereochemistries were not determined. Insome examples, an additional deprotection is required in the final step:

Compound no. MS (M + H)⁺ 1-305 577.4 1-306 590.3 1-310 590.4 1-311 562.41-315 563.4 1-316 563.4 1-317 570.5 1-320 582.2 1-323 578.4 1-326 604.41-342 589.4 1-343 589.4 1-345 598.4 1-346 604.5 1-347 604.4 1-350 588.41-355 577.4 1-356 577.4 1-360 584.3 1-361 638.3 1-362 603.3 1-365 595.31-372 604.4 1-373 604.3 1-375 603.4 1-381 630.6 1-383 609.3 1-386 604.41-387 603.4 1-389 652.5 1-391 604.4 1-393 608.2 1-402 651.5 1-404 609.31-409 595.5 1-412 595.6 1-413 596.6 1-414 594.5 1-418 638.5 1-419 636.41-420 622.3 1-421 635.3 1-422 613.4 1-423 627.4 1-424 612.3 1-426 626.41-427 618.4 1-433 617.4 1-434 618.4 1-435 617.3

Example 26:2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-307)

Step 26-1, preparation of2′-ethoxy-5-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclopentanecarbonyl]piperazin-1-yl]-N-[(3R)-1-[(5-methyl-2-oxo-2H-1,3-dioxol-4-yl)methyl]pyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:To a heterogeneous solution of Example 22 (50 mg, 0.085 mmol) andpotassium hydrogen carbonate (10 mg, 0.10 mmol) in DMF (1.5 mL) wasslowly added 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (20 mg, 0.10mmol) at rt. The resulting reaction was stirred at rt for 16 hours. Theinorganic solid was filtered off and then the filtrate was purified froma reverse phase C18 column chromatography to afford the title compound(18 mg, 30%). LCMS (M+H)⁺=701.4.

Example 27: (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(Compound 1-367) [*Absolute Stereochemistry not Determined]

Step 27-1, preparation of (2S*)-1,1,1-trifluoro-3,3-dimmethylbutan-2-yl1H-imidazole-1-carboxylate: to a solution of1,1,1-trifluoro-3,3-dimethylbutan-2-ol (100 mg, 0.640 mmol) in TH (3.0mL) was added 1-(1H-imidazole-1-carbonyl)-1H-imidazole (156 mg, 0.961mmol). The mixture was stirred at rt for 2.5 days. The mixture wasconcentrated to dryness and the residue was purified by silica gelcolumn chromatography to give the racemic mixture of title compound (145mg, 0.578 mmol, 90.3% yield) as a white solid. LCMS (M+H)⁺=251.1. Theracemic mixture was purified by following conditions to give theenantiomerically pure title compound (2^(nd) enantiomer: tentativeassignment).

Chiral Resolution Conditions:

Column: normal phase Daicel Chiralpak ID column, 20 mm ID×250 mm L, 5μm·particle sizeGradient: isocratic 5% EtOH in HexanesFlow rate: 20 mL/minRetention Times: 1^(st) enantiomer: 1.22 min (absolute stereochemistrynot determined; tentatively assigned as compound 1-366); 2^(nd)enantiomer: 1.52 min (absolute stereochemistry not determined;tentatively assigned as compound 1-367).

Step 27-2, preparation of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-amido}pyrrolidine-1-carboxylate:to a solution of tert-butyl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(181 mg, 0.274 mmol) from Step 21-1 in DCM (0.7 mL) was added TFA (0.38mL, 4.9 mmol). The resulting mixture was stirred at rt for 30 min andconcentrated in vacuo to dryness. The crude TFA salt was neutralizedwith saturated NaHCO₃ (aq) to give the title compound (153 mg, 0.274mmol, 100% yield) as a brown solid. LCMS (M+H)⁺=559.3.

Step 27-3, preparation of benzyl(2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate:to a solution of benzyl(3R)-3-{2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-[2,3′-bipyridin]-6-amido}pyrrolidine-1-carboxylate(110 mg, 0.197 mmol) in THE (5.0 mL) was added DIEA (0.270 mL, 1.55mmol) and (2S)-1,1,1-trifluoro-3,3-dimmethylbutane-2-yl1H-imidazole-1-carboxylate (75 mg, 0.30 mmol) in a sealed tube. Themixture was heated at 100° C. for 24 h. The mixture was concentrated todryness and the residue was purified by C18 reversed phase columnchromatography to give the title compound (120 mg, 0.162 mmol, 82.2%yield) as yellow oil. LCMS (M+H)⁺=741.4.

Step 27-4, preparation of (2S*)-1,1,1-trifluoro-3,3-dimethylbutane-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylateformate: to benzyl (2S*)-1,1,1-trifluoro-3,3-dimethylbutane-2-yl(3R)-4-(6-{[(3R)-1-[(benzyloxy)carbonyl]pyrrolidin-3-yl]carbamoyl}-2′-ethoxy-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(120 mg, 0.162 mmol) was added TFA (2.0 mL). The resulting mixture washeated at 60° C. for 2 h. The reaction mixture was purified by C18reversed phase column chromatography to give the title compound (72.0mg, 0.110 mmol, 67.9% yield) as a white solid. LCMS (M+H)⁺=597.4.

The following compounds were prepared similarly to Example 27 withappropriate substituting reagents and substrates at different steps.Some examples' absolute stereochemistries were not determined. In someexamples, an additional deprotection is not required in the final step:

Compound no. MS (M + H)⁺ 1-309 579.4 1-312 607.3 1-338 590.4 1-348 606.31-351 627.3  1-366* 607.4 1-369 619.3 1-377 627.2  1-396* 621.4  1-403*647.4  1-407* 606.3 *absolute stereochemistry not determined

Example 28: (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate(Compound 1-392) [*Absolute Stereochemistry not Determined]

Step 28-1, preparation of (2S*)-1,1,1-trifluoro-3,3-dimethylbutan-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-1-methylpyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylate:to a solution of (2S)-1,1,1-trifluoro-3,3-dimethylbutane-2-yl(3R)-4-(2′-ethoxy-6-{[(3R)-pyrrolidin-3-yl]carbamoyl}-[2,3′-bipyridin]-5-yl)-3-ethylpiperazine-1-carboxylateformate (40.0 mg, 0.0613 mmol) in MeOH (3.0 mL) was addedparaformaldehyde (38.5 mg) and sodium cyanoborohydride (38.5 mg, 0.613mmol). The resulting mixture was stirred at rt for 1 h. The reactionmixture was quenched by TFA (0.1 mL) and re-basified with saturatedNaHCO₃ (aq). The mixture was extracted with DCM and the organic layerwas concentrated in vacuo to dryness. The residue was purified by C18reversed phase column chromatography to give the title compound (26.1mg, 0.0420 mmol, 68.5% yield) as an off-white solid. LCMS (M+H)⁺=621.5.

The following compounds were prepared similarly to Example 28 withappropriate substituting reagents and substrates at different steps.Some examples' absolute stereochemistries were not determined:

Compound no. MS (M + H)⁺ 1-370 621.4 1-376 621.5 1-384 613.3 1-397 579.4 1-406* 621.5 1-408 629.6 *absolute stereochemistry not determined

Example 29:5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-438)

Step 29-1, preparation of 5-fluoro-1H-indole-7-carbonitrile: to amixture of 7-bromo-5-fluoro-1H-indole (920 mg, 4.30 mmol), dicyanozinc(1.514 g, 12.89 mmol) and Pd(PPh₃)₄ (993 mg, 0.860 mmol) in a sealedtube was added DMF (10 mL). Nitrogen (g) was bubbled through thereaction mixture. The resulting mixture was heated at 120° C. for 16 h.The mixture was quenched by water and extracted with DCM (3×). Thecombined organics were concentrated to dryness and the residue waspurified by C18 reversed phase column chromatography to give the titlecompound (676 mg, 4.22 mmmol, 98% yield) as an off-white solid.

Step 29-2, preparation of 4-nitrophenyl7-cyano-5-fluoro-1H-indole-1-carboxylate: to a suspension of5-fluoro-1H-indole-7-carbonitrile (306 mg, 1.91 mmol) and 4-nitrophenylcarbonochloridate (463 mg, 2.30 mmol) in THF (20 mL) was added TEA (0.80mL, 5.74 mmol) and DMAP (23.4 mg, 0.191 mmol). The resulting mixture wasstirred at rt for 2 h but the reaction was not complete. More4-nitrophenyl carbonochloridate (463 mg, 2.30 mmol) and triethylamine(0.80 mL, 5.73 mmol) were added and the reaction was continued for 2 h.The mixture was concentrated to dryness and the residue was purified bysilica gel column chromatography to give the title compound (411 mg,1.26 mmol, 66% yield) as an off-white solid.

Step 29-3, preparation of5-[(2R)-4-(7-cyano-5-fluoro-1H-indole-1-carbonyl)-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidefrom Example 20, Step 3 (50.0 mg, 0.114 mmol) and 4-nitrophenyl7-cyano-5-fluoro-1H-indole-1-carboxylate (44.5 mg, 0.137 mmol) in MeCN(1 mL) was added DMAP (34.8 mg, 0.285 mmol). The mixture was heated at50° C. for 1 h. The mixture was purified by C18 reversed phase columnchromatography to give the title compound (14.5 mg, 0.023 mmol, 20%yield) as a light yellow solid. LCMS (M+H)⁺=625.4.

The following compounds were prepared similarly to Example 29 withappropriate substituting reagents and substrates at different steps.

Compound no. MS (M + H)⁺ 1-425 634.1 1-428 616.2 1-429 607.4 1-430 633.31-431 615.2 1-432 606.3 1-436 650.5 1-437 649.4 1-439 624.3

Example 30:5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide(Compound 1-261)

Step 30-1, preparation of5-[(2R)-4-[2-chloro-4-fluorobenzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamide:to a solution of 2-chloro-4-fluorobenzoic acid (35.9 mg, 0.206 mmol) andHATU (73.0 mg, 0.192 mmol) in DMF (0.2 mL) was added DIEA (0.072 mL,0.41 mmol). After stirring at rt for 5 min, this HATU-activated solutionwas added to a solution of2′-ethoxy-5-[(2R)-2-ethylpiperazin-1-yl]-N-[(3R)-1-methylpyrrolidin-3-yl]-[2,3′-bipyridine]-6-carboxamidetris(2,2,2-trifluoroacetate) from Example 20, Step 3 (107 mg, 0.137mmol) and DIEA (0.072 mL, 0.41 mmol) in DMF (0.2 mL). The resultingmixture was stirred at rt for 10 min. The reaction mixture was purifiedby C18 reversed phase column chromatography to give the title compound(39.4 mg, 0.0645 mmol, 47% yield) as a light yellow solid. LCMS(M+H)⁺=595.5.

Example 31:N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide(Compound 1-410)

Step 31-1, preparation of6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxylicacid: to a solution of3-[(2R)-4-[(tert-butoxy)carbonyl]-2-ethylpiperazin-1-yl]-6-(2-ethoxyphenyl)pyridine-2-carboxylicacid (450 mg, 0.98 mmol) from Example 25, step 3 in DCM (5.0 mL) wasadded TFA (1.14 mL, 14.8 mmol) at rt. The resulting solution was stirredat rt for 1 h and concentrated under vacuum to afford6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylicacid. This residue was dissolved in ACN (2 mL) and neutralized with Et₃N(0.3 mL). The solution was used in the next HATU coupling step withoutfurther purification.

To a solution of 1-(trifluoromethyl)cyclobutane-1-carboxylic acid (332mg, 1.98 mmol) in ACN (5 mL) was added HATU (751 mg, 1.98 mmol) andfollowed by Et₃N (0.26 mL, 1.98 mmol) at rt. After stirring at rt for 5min, this HATU-activated solution was treated with the solution of6-(2-ethoxyphenyl)-3-[(2R)-2-ethylpiperazin-1-yl]pyridine-2-carboxylicacid described above. The resulting mixture was stirred at rt for 30 minand concentrated under vacuum. The residue was purified by C18 reversedphase column chromatography to give the title compound (290 mg, 58%yield). LCMS (M+H)⁺=506.3.

Step 31-2, preparation ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxamide:to a solution of6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-1-yl]pyridine-2-carboxylicacid (70 mg, 0.14 mmol) and HATU (58.0 mg, 0.15 mmol) in DMF (1.5 mL)was added Et₃N (0.074 mL, 0.55 mmol). After stirring at rt for 5 min,the resulting solution was treated with (S)-quinuclidin-3-aminedihydrochloride (33 mg, 0.17 mmol). The resulting mixture was stirred atrt for 1 hr and directly purified by C18 reversed phase columnchromatography to give the title compound (40 mg, 47% yield). LCMS(M+H)⁺=614.3.

Example A-1: Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 1-100 mg of awater-soluble salt of a compound Formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, is dissolved in sterile water andthen mixed with 10 mL of 0.9% sterile saline. A suitable buffer isoptionally added as well as optional acid or base to adjust the pH. Themixture is incorporated into a dosage unit form suitable foradministration by injection

Example A-2: Oral Solution

To prepare a pharmaceutical composition for oral delivery, a sufficientamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, is added to water (with optional solubilizer(s), optionalbuffer(s) and taste masking excipients) to provide a 20 mg/mL solution.

Example A-3: Oral Tablet

A tablet is prepared by mixing 20-50% by weight of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, 20-50% by weight ofmicrocrystalline cellulose, 1-10% by weight of low-substitutedhydroxypropyl cellulose, and 1-10% by weight of magnesium stearate orother appropriate excipients. Tablets are prepared by directcompression. The total weight of the compressed tablets is maintained at100-500 mg.

Example A-4: Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 10-500 mg ofa compound of Formula (I), or a pharmaceutically acceptable saltthereof, is mixed with starch or other suitable powder blend. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 10-500 mg of a compound of Formula (I), or apharmaceutically acceptable salt thereof, is placed into Size 4 capsule,or size 1 capsule (hypromellose or hard gelatin) and the capsule isclosed.

Example A-5: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, is mixedwith hydroxypropyl celluose, propylene glycol, isopropyl myristate andpurified alcohol USP. The resulting gel mixture is then incorporatedinto containers, such as tubes, which are suitable for topicaladministration.

Example B-1: MC2R Assays Membrane Preparation:

Crude membrane fractions are prepared from CRE-bla-CHO-K1 cells stablyexpressing hMC2 receptor and hMRAP accessory protein (Thermo Fisher).The cells are grown to 85-100% confluence on standard tissue culturedishes in GlutaMax DMEM growth media (Gibco) with following additives:10% dialyzed FBS (Gemini), 0.1 mM NEAA (Gibco), 25 mM HEPES (Gibco), 5μg/mL blasticidin (Goldbio), 100 μg/mL zeocin (Invitrogen), 600 μg/mLhygromycin (Goldbio). To prepare membranes, cells are scraped andcollected in 1× Dulbecco's phosphate buffered saline (Corning) and thenpelleted at 1000 RPM's. The cell pellet is reconstituted in membranepreparation buffer (20 mM HEPES, 6 mM MgCl₂ and 1 mM EGTA, proteaseinhibitor tablets (Pierce) adjusted to pH 7.4), homogenized using adounce homogenizer, and the resulting membrane fraction is pelleted bycentrifugation at 12,000 RPM's. The membrane pellet is resuspended inmembrane preparation buffer, snap freezed and stored at −80° C. forlater use.

Binding Assay for hMC2 Antagonists Protocol:

The hMC2 membrane binding assay utilizes the following components:radiolabel [¹²⁵I]ACTH (1-39) Tyr23 (PerkinElmer), wheatgerm agglutinincoated PVT SPA beads (PerkinElmer), crude hMC2R membranes, andcompounds. Briefly hMC2R membranes are incubated with SPA beads inbinding assay buffer (50 mM HEPES, 5 mM MgCl₂, 1 mM CaCl₂, 0.2% BSA,protease inhibitor tablets (Pierce) adjusted to pH7.4) prior to assayinitiation. A dose response of compound (the final concentration ofcompound are typically 0-10,000 nM), SPA membranes, and [¹²⁵I]ACTH(1-39) Tyr23 at a final concentration of 0.2 nM is plated in a 96-wellassay plate and allowed to incubate 1.5 hours at room temperature. Assayplates are read using a Top Count NXT and K_(i) values for compounds aredetermined using a GraphPad Prism 6 non-linear regression analysis.

Illustrative binding affinities of selective compounds are described inTable A. The potencies are divided into four criteria: + means thatK_(i) is between 1,000 nM and 10,000 nM; ++ means that K_(i) is between100 nM and 1,000 nM; +++ means K_(i) is between 10 nM and 100 nM; ++++means K_(i) is below 10 nM.

TABLE A Compound No. MC2R binding potency 1-1  +++ 1-2  ++++ 1-3  ++++1-4  +++ 1-5  +++ 1-6  +++ 1-7  +++ 1-8  +++ 1-9  +++ 1-11  +++ 1-15 ++++ 1-16  +++ 1-17  ++++ 1-18  ++++ 1-19  +++ 1-20  +++ 1-23  +++ 1-24 ++++ 1-25  ++++ 1-26  ++++ 1-27  ++++ 1-32  +++ 1-33  +++ 1-34  ++++1-35  ++++ 1-36  ++++ 1-37  ++++ 1-38  ++++ 1-40  ++++ 1-41  ++++ 1-42 ++++ 1-43  ++++ 1-44  ++++ 1-45  ++++ 1-46  ++++ 1-47  ++++ 1-48  ++++1-49  ++++ 1-50  ++++ 1-51  ++++ 1-52  ++++ 1-54  ++++ 1-57  ++++ 1-58 ++++ 1-59  ++++ 1-60  ++++ 1-62  ++++ 1-67  ++++ 1-68  ++++ 1-69  ++++1-71  ++++ 1-72  ++++ 1-73  ++++ 1-76  ++++ 1-82  ++++ 1-84  ++++ 1-87 ++++ 1-88  ++++ 1-90  ++++ 1-91  ++++ 1-92  ++++ 1-93  ++++ 1-94  ++++1-95  ++++ 1-96  ++++ 1-97  ++++ 1-98  ++++ 1-99  ++++ 1-100 ++++ 1-101++++ 1-102 ++++ 1-104 ++++ 1-107 ++++ 1-108 ++++ 1-109 ++++ 1-110 ++++1-111 ++++ 1-112 ++++ 1-113 ++++ 1-114 ++++ 1-115 ++++ 1-116 ++++ 1-117++++ 1-123 ++++ 1-124 ++++ 1-125 ++++ 1-136 ++++ 1-137 ++++ 1-138 ++++1-142 ++++ 1-143 ++++ 1-148 ++++ 1-149 ++++ 1-150 ++++ 1-151 ++++ 1-152++++ 1-155 ++++ 1-156 ++++ 1-163 ++++ 1-164 ++++ 1-165 ++++ 1-167 ++++1-168 ++++ 1-169 ++++ 1-170 ++++ 1-171 ++++ 1-173 ++++ 1-174 ++++ 1-176++++ 1-177 ++++ 1-178 ++++ 1-181 ++++ 1-182 ++++ 1-183 ++++ 1-184 ++++1-187 ++++ 1-188 ++++ 1-189 ++++ 1-190 ++++ 1-198 ++++ 1-199 ++++ 1-200++++ 1-201 ++++ 1-202 ++++ 1-203 ++++ 1-206 ++++ 1-207 ++++ 1-208 ++++1-209 ++++ 1-210 ++++ 1-211 ++++ 1-212 ++++ 1-213 ++++ 1-214 ++++ 1-215++++ 1-216 ++++ 1-219 ++++ 1-220 ++++ 1-221 ++++ 1-222 ++++ 1-223 ++++1-224 ++++ 1-225 ++++ 1-226 ++++ 1-227 ++++ 1-228 ++++ 1-229 ++++ 1-230++++ 1-231 ++++ 1-232 ++++ 1-233 ++++ 1-234 ++++ 1-236 ++++ 1-237 ++++1-238 ++++ 1-239 ++++ 1-240 ++++ 1-241 ++++ 1-242 ++++ 1-243 ++++ 1-244++++ 1-245 ++++ 1-246 ++++ 1-247 ++++ 1-249 ++++ 1-253 ++++ 1-254 ++++1-255 ++++ 1-256 ++++ 1-257 ++++ 1-258 ++++ 1-259 ++++ 1-260 ++++ 1-261++++ 1-262 ++++ 1-263 ++++ 1-264 ++++ 1-265 ++++ 1-266 ++++ 1-267 ++++1-270 ++++ 1-271 ++++ 1-273 ++++ 1-274 ++++ 1-275 ++++ 1-276 ++++ 1-277++++ 1-278 ++++ 1-279 ++++ 1-280 ++++ 1-282 ++++ 1-283 ++++ 1-286 ++++1-287 ++++ 1-288 ++++ 1-289 ++++ 1-290 ++++ 1-291 ++++ 1-292 ++++ 1-293++++ 1-296 ++++ 1-297 ++++ 1-298 ++++ 1-299 ++++ 1-304 ++++ 1-305 ++++1-306 ++++ 1-312 ++++ 1-313 ++++ 1-314 ++++ 1-315 ++++ 1-320 ++++ 1-321++++ 1-324 ++++ 1-325 ++++ 1-326 ++++ 1-327 ++++ 1-328 ++++ 1-329 ++++1-330 ++++ 1-331 ++++ 1-332 ++++ 1-333 ++++ 1-334 ++++ 1-335 ++++ 1-336++++ 1-337 ++++ 1-338 ++++ 1-339 ++++ 1-340 ++++ 1-341 ++++ 1-342 ++++1-343 ++++ 1-344 ++++ 1-345 ++++ 1-346 ++++ 1-348 ++++ 1-349 ++++ 1-350++++ 1-351 ++++ 1-352 ++++ 1-353 ++++ 1-354 ++++ 1-356 ++++ 1-357 ++++1-358 ++++ 1-360 ++++ 1-361 ++++ 1-362 ++++ 1-363 ++++ 1-365 ++++ 1-367* ++++ 1-368 ++++ 1-371 ++++ 1-372 ++++ 1-373 ++++ 1-374 ++++1-375 ++++ 1-376 ++++ 1-377 ++++ 1-378 ++++ 1-380 ++++ 1-381 ++++ 1-382++++ 1-383 ++++ 1-385 ++++ 1-386 +++ 1-387 ++++ 1-388 ++++ 1-389 ++++1-390 +++ 1-391 ++++  1-392* ++++ 1-393 ++++ 1-394 ++++ 1-395 ++++ 1-396* ++++ 1-397 ++++ 1-398 ++++ 1-399 ++++ 1-400 ++++ 1-401 ++++1-402 ++++  1-403* ++++ 1-404 ++++ 1-405 ++++  1-406* ++++  1-407* ++++1-408 ++++ 1-409 ++++ 1-410 ++++ 1-411 ++++ 1-412 ++++ 1-413 ++++ 1-414++++ 1-415 ++++ 1-416 ++++ 1-417 ++++ 1-418 ++++ 1-419 ++++ 1-420 ++++1-421 ++++ 1-422 ++++ 1-423 ++++ 1-424 ++++ 1-425 ++++ 1-426 ++++ 1-427++++ 1-428 ++++ 1-429 ++++ 1-430 ++++ 1-431 ++++ 1-432 ++++ 1-433 ++++1-434 ++++ 1-435 ++++ 1-436 ++++ 1-437 ++++ 1-438 ++++ 1-439 ++++ 2-2 ++++ 2-3  +++ 2-13  ++++ 2-16  ++++ 2-20  ++++ 2-21  ++++ 2-25  ++++2-30  ++++ 2-31  ++++ *absolute stereochemistry not determined

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

1. A compound of Formula (IX), or a pharmaceutically acceptable salt, orsolvate thereof:

wherein: V is CH; R^(a) is selected from the group consisting ofhydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,unsubstituted or substituted C₁-C₆ heteroalkyl, and unsubstituted orsubstituted C₃-C₆ cycloalkyl, wherein any substituted group of R^(a) issubstituted with one or more R⁹ groups; R^(b) and R^(c) are eachindependently selected from the group consisting of hydrogen, halogen,—OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ fluoroalkyl, and unsubstituted orsubstituted C₁-C₆ heteroalkyl, wherein any substituted group of R^(b)and R^(c) is substituted with one or more R⁹ groups; R^(B) isunsubstituted or substituted carbocycle, unsubstituted or substitutedheterocycle, unsubstituted or substituted C₁-C₇ alkyl, unsubstituted orsubstituted C₁-C₇ fluoroalkyl, or unsubstituted or substituted C₁-C₆heteroalkyl, wherein if R^(B) is substituted then R^(B) is substitutedwith R^(d), R^(e) and R^(f); R^(d) is selected from the group consistingof hydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl,unsubstituted or substituted C₁-C₆ heteroalkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, unsubstituted or substituted C₂-C₇heterocycloalkyl, unsubstituted or substituted phenyl, and unsubstitutedor substituted monocyclic heteroaryl, wherein any substituted group ofR^(d) is substituted with one or more R⁹ groups; R^(e) and R^(f) areeach independently selected from the group consisting of hydrogen,halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₁-C₆ fluoroalkyl, and unsubstituted orsubstituted C₁-C₆ heteroalkyl, wherein any substituted group of R^(d) issubstituted with one or more R⁹ groups; X¹ is CR⁶; R² and R³ arehydrogen; or R² and R³ are taken together with the carbon atom to whichthey are attached to form —C(═O)—; R⁴ is selected from the groupconsisting of hydrogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted monocyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substituted —(C₁-C₆alkyl)-carbocycle, and unsubstituted or substituted —(C₁-C₆alkyl)-heterocycle, wherein any substituted group of R⁴ is substitutedwith one or more halogen, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted monocyclic heterocycle, —N(R⁷)₂, —OR⁸, —CN,—CO₂R⁸, —C(═O)N(R⁷)₂, —SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸,—NR⁷SO₂R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; R⁶ is H or F; each R⁷ isindependently selected from the group consisting of hydrogen,substituted C₁-C₆ alkyl, unsubstituted or substituted C₃-C₆ cycloalkyl,unsubstituted or substituted C₁-C₆fluoroalkyl, unsubstituted orsubstituted aryl, and unsubstituted or substituted heteroaryl; or two R⁷are taken together with the nitrogen atom to which they are attached toform an unsubstituted or substituted 3- to 6-membered monocyclicheterocycle; each R⁸ is independently selected from the group consistingof hydrogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₃-C₆ cycloalkyl, unsubstituted or substitutedC₁-C₆fluoroalkyl, unsubstituted or substituted aryl, and unsubstitutedor substituted heteroaryl; each R⁹ is independently hydrogen, halogen,unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substitutedC₁-C₄alkoxy, unsubstituted or substituted C₁-C₄fluoroalkyl,unsubstituted or substituted C₁-C₄fluoroalkoxy, unsubstituted orsubstituted monocyclic carbocycle, unsubstituted or substitutedmonocyclic heterocycle, —CN, —OH, —CO₂R⁸, —CH₂CO₂R⁸, —C(═O)N(R⁷)₂,—C(═O)N(R⁷)OR⁸, —CH₂C(═O)N(R⁷)₂, —N(R⁷)₂, —CH₂N(R⁷)₂, —C(R⁸)₂N(R⁷)₂,—NR⁷C(═O)R⁸, —CH₂NR⁷C(═O)R⁸, —NR⁷C(═O)N(R⁷)₂, —NR⁷C(═O)N(R⁷)₂,C(R⁸)═N(R⁷)—OR⁸, —SR⁸, —S(═O)R¹⁰, —SO₂R¹⁰, or —SO₂N(R⁷)₂; and each R¹⁰is independently selected from the group consisting unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted C₃-C₆ cycloalkyl,unsubstituted or substituted C₁-C₆fluoroalkyl, unsubstituted orsubstituted phenyl, and unsubstituted or substituted heteroaryl.
 2. Thecompound of claim 1, or a pharmaceutically acceptable salt, or solvatethereof, wherein: R^(a) is selected from the group consisting ofhydrogen, halogen, —OR⁸, —CN, —N(R⁷)₂, unsubstituted or substitutedC₁-C₆ alkyl, unsubstituted or substituted C₁-C₆ fluoroalkyl, andunsubstituted or substituted C₁-C₆ heteroalkyl, wherein any substitutedgroup of R^(a) is substituted with one or more R⁹ groups; and R^(b) andR^(c) are each independently selected from the group consisting ofhydrogen, halogen, —OR⁸, —N(R⁷)₂, and unsubstituted or substituted C₁-C₆alkyl, wherein any substituted group of R^(b) and R^(c) is substitutedwith one or more R⁹ groups.
 3. The compound of claim 2, or apharmaceutically acceptable salt, or solvate thereof, wherein: R^(a) is—OR⁸; and R^(b) and R^(c) are each hydrogen.
 4. The compound of claim 1,or a pharmaceutically acceptable salt, or solvate thereof, wherein: R⁴is selected from the group consisting of hydrogen, unsubstituted orsubstituted C₁-C₆ alkyl, unsubstituted or substituted monocycliccarbocycle, and unsubstituted or substituted monocyclic 4-, 5-, or6-membered heterocycle containing 1-4 N atoms and 0 or 1 O or S atoms,wherein any substituted group of R⁴ is substituted with one or morehalogen, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted monocyclic 4-, 5- or 6-membered heterocycle containing 1-4 Natoms and 0 or 1 O or S atoms, —N(R⁷)₂, —OR⁸, —CN, —CO₂R⁸, —C(═O)N(R⁷)₂,—SR⁸, —S(═O)R¹⁰, —S(═O)₂R¹⁰, —NR⁷C(═O)R⁸, —NR⁷SO₂R¹⁰, —SO₂R¹⁰, or—SO₂N(R⁷)₂.
 5. The compound of claim 4, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: R⁴ is an unsubstituted or substitutedmonocyclic 4-, 5- or 6-membered heterocycle containing 1-2 N atoms and 0or 1 O or S atoms, wherein any substituted group of R⁴ is substitutedwith one or more halogen, unsubstituted or substituted C₁-C₆ alkyl,—N(R⁷)₂, —OR⁸, or —CN.
 6. The compound of claim 4, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: R⁴ is hydrogen.
 7. Thecompound of claim 1, or a pharmaceutically acceptable salt, or solvatethereof, wherein: R^(B) is an unsubstituted or substituted monocycliccarbocycle, unsubstituted or substituted bicyclic carbocycle,unsubstituted or substituted polycyclic carbocycle, unsubstituted orsubstituted monocyclic heterocycle, unsubstituted or substitutedbicyclic heterocycle, or unsubstituted or substituted polycyclicheterocycle, wherein if R^(B) is substituted then R^(B) is substitutedwith R^(d), R^(e) and R^(f).
 8. The compound of claim 7, or apharmaceutically acceptable salt, or solvate thereof, wherein: R^(B) isan unsubstituted or substituted phenyl, unsubstituted or substitutednaphthyl, unsubstituted or substituted monocyclic 6-membered heteroaryl,unsubstituted or substituted monocyclic 5-membered heteroaryl,unsubstituted or substituted bicyclic heteroaryl, monocyclicC₃-C₈cycloalkyl, unsubstituted or substituted bridged C₅-C₁₀cycloalkyl,unsubstituted or substituted monocyclic C₂-C₈heterocycloalkyl, orunsubstituted or substituted bridged C₅-C₁₀heterocycloalkyl, wherein ifR^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f).
 9. The compound of claim 8, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: R^(B) is unsubstituted or substitutedphenyl, unsubstituted or substituted monocyclic 6-membered heteroaryl,unsubstituted or substituted monocyclic 5-membered heteroaryl,unsubstituted or substituted bicyclic heteroaryl, monocyclicC₃-C₈cycloalkyl, or unsubstituted or substituted monocyclicC₂-C₈heterocycloalkyl, wherein if R^(B) is substituted then R^(B) issubstituted with R^(d), R^(e) and R^(f).
 10. The compound of claim 9, ora pharmaceutically acceptable salt, or solvate thereof, wherein: R^(B)is

where Z is CH or N.
 11. The compound of claim 9, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein: R^(B) is unsubstituted orsubstituted cyclopropyl, unsubstituted or substituted cyclobutyl,unsubstituted or substituted cyclopentyl, unsubstituted or substitutedcyclopentenyl, or unsubstituted or substituted cyclohexyl, wherein ifR^(B) is substituted then R^(B) is substituted with R^(d), R^(e) andR^(f).
 12. The compound of claim 9, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: R^(B) is

where m is 0, 1, 2, or
 3. 13. The compound of claim 1, or apharmaceutically acceptable salt, or solvate thereof, wherein: R^(d) isselected from the group consisting of hydrogen, halogen, —OR⁸, —CN,—N(R⁷)₂, unsubstituted or substituted C₁-C₆ alkyl, unsubstituted orsubstituted C₁-C₆ fluoroalkyl, and unsubstituted or substituted C₁-C₆heteroalkyl, wherein any substituted group of R^(d) is substituted withone or more R⁹ groups; and R^(e) and R^(f) are each independentlyselected from the group consisting of hydrogen, halogen, —OR⁸, —CN,—N(R⁷)₂, and unsubstituted or substituted C₁-C₆ alkyl, wherein anysubstituted group of R^(e) and R^(f) is substituted with one or more R⁹groups.
 14. The compound of claim 1, or a pharmaceutically acceptablesalt, or solvate thereof, wherein: each R⁷ is independently selectedfrom the group consisting of hydrogen, substituted C₁-C₆ alkyl,unsubstituted or substituted C₃-C₆ cycloalkyl, and unsubstituted orsubstituted C₁-C₆fluoroalkyl; or two R⁷ are taken together with thenitrogen atom to which they are attached to form an unsubstituted orsubstituted 3- to 6-membered monocyclic heterocycle; each R⁸ isindependently selected from the group consisting of hydrogen,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₃-C₆ cycloalkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl;each R⁹ is independently hydrogen, halogen, unsubstituted or substitutedC₁-C₄alkyl, unsubstituted or substituted C₁-C₄alkoxy, unsubstituted orsubstituted C₁-C₄fluoroalkyl, unsubstituted or substitutedC₁-C₄fluoroalkoxy, unsubstituted or substituted monocyclic carbocycle,unsubstituted or substituted monocyclic heterocycle, —CN, —OH, —CO₂R⁸,—CH₂CO₂R⁸, —C(═O)N(R⁷)₂, —CH₂C(═O)N(R⁷)₂, —N(R⁷)₂, —CH₂N(R⁷)₂,—NR⁷C(═O)R⁸, or —CH₂NR⁷C(═O)R⁸; and each R¹⁰ is independently selectedfrom the group consisting unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₃-C₆ cycloalkyl, unsubstituted orsubstituted C₁-C₆fluoroalkyl, and unsubstituted or substituted phenyl.15. The compound of claim 1, or a pharmaceutically acceptable salt, orsolvate thereof, wherein the compound of Formula (IX) has the structureof Formula (IXa), or a pharmaceutically acceptable salt, or solvatethereof:


16. (canceled)
 17. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt, or solvate thereof, andat least one pharmaceutically acceptable excipient.
 18. A method ofmodulating melanocortin subtype-2 receptor (MC2R) activity in a mammal,comprising administering a compound of claim 1, or a pharmaceuticallyacceptable salt, or solvate thereof, to the mammal in need thereof. 19.A method of treating a disease or condition in a mammal that wouldbenefit from the modulation of melanocortin subtype-2 receptor (MC2R)activity, comprising administering a compound of claim 1, or apharmaceutically acceptable salt, or solvate thereof, to the mammal inneed thereof, wherein the disease or condition comprises growth of fatpads in the collarbone, back of neck, face and trunk, excessivesweating, dilation of capillaries, thinning of the skin, muscleweakness, hirsutism, depression, anxiety, hypertension, osteoporosis,insulin resistance, hyperglycemia, heart disease, or combinationsthereof.
 20. The method of claim 19, wherein the disease or condition isCushing's syndrome.
 21. The compound of claim 1, wherein the compound isselected from: 1-1:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′,3′-difluoro-[1,1′-biphenyl]-3-carboxamide;1-2:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methoxy-[1,1′-biphenyl]-3-carboxamide;1-3:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-4:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-fluoro-[1,1′-biphenyl]-3-carboxamide;1-5:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethyl-[1,1′-biphenyl]-3-carboxamide;1-6:N-(2-aminoethyl)-2′-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-carboxamide;1-7:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyano-[1,1′-biphenyl]-3-carboxamide;1-8:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methyl-[1,1′-biphenyl]-3-carboxamide;1-9:N-(2-aminoethyl)-2′-chloro-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3′-fluoro-[1,1′-biphenyl]-3-carboxamide;1-10:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-3′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-11:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propoxy-[1,1′-biphenyl]-3-carboxamide;1-12:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-(propan-2-yloxy)-[1,1′-biphenyl]-3-carboxamide;1-13:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-hydroxy-[1,1′-biphenyl]-3-carboxamide;1-14:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-cyclopropoxy-[1,1′-biphenyl]-3-carboxamide;1-15:(R)—N-(2-aminoethyl)-4-(4-(2,4-dichlorobenzoyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-16:(R)—N-(2-aminoethyl)-4-(4-(2-chloro-4-(trifluoromethyl)benzoyl)-2-ethylpiperazin-1-yl)-2′-(methoxymethyl)-[1,1′-biphenyl]-3-carboxamide;1-17:(R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-18:(R)—N-(2-aminoethyl)-4-(4-(4′-(aminomethyl)-5-methyl-[1,1′-biphenyl]-2-carbonyl)-2-ethylpiperazin-1-yl)-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-22:N-(2-aminoethyl)-2′-(aminomethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-3-carboxamide;1-23:N-(3-aminopropyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-24:N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-25:N-(2-aminoethyl)-4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-26:N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-3′-fluoro-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-27:N-(2-aminoethyl)-4-[(2R)-4-[4′-(aminomethyl)-3-fluoro-5-methyl-[1,1′-biphenyl]-2-carbonyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-carboxamide;1-28:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propyl-[1,1′-biphenyl]-3-carboxamide;1-29:N-(2-aminoethyl)-4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-4′-propyl-[1,1′-biphenyl]-3-carboxamide;2-1:2-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]ethan-1-ol;2-2:(2S)-1-[({4-[(2R)-4-[2-chloro-4-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-ethoxy-[1,1′-biphenyl]-3-yl}methyl)amino]propan-2-ol;2-3:1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-methoxy-[1,1′-biphenyl]-3-yl}methanamine;2-4:1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-(2-methoxyethoxy)-[1,1′-biphenyl]-3-yl}methanamine;2-5:1-{4-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-2′-propoxy-[1,1′-biphenyl]-3-yl}methanamine;2-6:2-{[3′-(aminomethyl)-4′-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-2-yl]oxy}ethan-1-ol;2-7:2-{[3′-(aminomethyl)-4′-[(2R)-2-ethyl-4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1′-biphenyl]-2-yl]oxy}ethan-1-ol;2-8:[3′-(aminomethyl)-4′-[(2R)-4-[4-chloro-2-(trifluoromethyl)benzoyl]-2-ethylpiperazin-1-yl]-[1,1′-biphenyl]-2-yl]methanol;2-26:1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-3′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;2-27:1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-[1,1′-biphenyl]-3-yl}methanamine;2-28:1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-4′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;and 2-29:1-{2′-ethoxy-4-[(2R)-2-ethyl-4-[4-methyl-2-(trifluoromethyl)benzoyl]piperazin-1-yl]-5′-fluoro-[1,1′-biphenyl]-3-yl}methanamine;or a pharmaceutically acceptable salt, or solvate thereof.